Customizable facility

ABSTRACT

A campus for fabricating at least one pharmaceutical product has one or more customizable facilities each configured to manufacture the at least one pharmaceutical product, a media/buffer plant, and a utility building connected by a utility line to the media/buffer plant and/or the one or more customizable facilities to provide at least one first utility to the media/buffer plant and/or the one or more customizable facilities via the utility line.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/659,390, filed Jul. 25, 2017, which is a continuation-in-part of U.S.patent application Ser. No. 15/455,836, filed on Mar. 10, 2017, whichclaims the benefit of priority to U.S. Provisional Patent ApplicationSer. No. 62/306,556, filed on Mar. 10, 2016, and U.S. Provisional PatentApplication Ser. No. 62/370,041, filed on Aug. 2, 2016, each of which ishereby incorporated herein by reference in its entirety for allpurposes.

FIELD OF THE INVENTION

The present disclosure relates to a customizable facility that enables auser to manufacture multiple products within the facility. Inparticular, the present disclosure relates to a customizable facilityfor manufacturing products in clean room settings.

BACKGROUND

Traditional structures for manufacturing products, such as monoclonalantibodies and microbial products, do not allow for efficient use of thespace of the structure. The layout of traditional structures oftenlimits them from being readily configured or expanded to manufacture anew product line. Thus, there is a need for a manufacturing facilitythat allows a user to efficiently use common resources between productlines and readily modify the facility to accommodate a new manufacturingprocess or a new manufacturing line with reduced facility down time.

SUMMARY

The present disclosure provides a customizable facility formanufacturing at least one product, utilizing at least one productionprocess (e.g., a production process using a fermentation unit and apurification unit). According to one aspect of the present disclosure,the customizable facility includes a shell, at least one central unitpositioned within the shell, and at least one modular unit, each modularunit being positioned within the shell. The shell, the central unit(s),and the modular unit(s) are configured and arranged to maximize thespeed and ease of modifying manufacturing capacity of varying scope.

According to another aspect of the present disclosure, a customizablefacility for manufacturing at least one pharmaceutical product, includesat least one central unit. At least one modular unit is in communicationwith the at least one central unit such that the at least one centralunit provides utilities to the at least one modular unit.

In some embodiments, the customizable facility includes a shell, whereinthe at least one central unit is positioned at least partially withinthe shell and the at least one modular unit is positioned at leastpartially within the shell.

In some embodiments, the at least one modular unit includes at least oneof a fermentation unit, a pre-viral unit, a post-viral unit, a utilityspace, a warehouse, a media buffer facility, an office, a personnelunit, a production unit, a fill-finish unit, a dosage formulation unit,and a packaging unit.

In some embodiments, at least one of the at least one modular unit isdirectly adjacent to the at least one central unit.

In some embodiments, the at least one modular unit includes a pluralityof modular units arranged to maximize a number of modular units withinthe shell while minimizing a footprint of the shell.

In some embodiments, each modular unit of the plurality of modular unitsis directly adjacent at least one of the at least one central unit andanother one of the plurality of modular units.

In some embodiments, the at least one central unit and the plurality ofmodular units form a hub and spoke formation.

In some embodiments, the at least one central unit and the plurality ofmodular units are arranged in an H-shaped layout.

In some embodiments, the customizable facility includes a bioreactorsupported on a ground surface within the shell.

In some embodiments, the customizable facility includes a bioreactorsupported within one of the at least one modular unit.

In some embodiments, an outer wall of the customizable facility is oneof: formed by the shell, the shell entirely enclosing the at least onecentral unit and the at least one modular unit; and formed by the shelland at least one of an outer wall of the at least one central unit andan outer wall of the at least one modular unit.

In some embodiments, the shell includes at least one side wall, the atleast one side wall encircling the at least one central unit and the atleast one modular unit, and a roof secured to an upper edge of the atleast one side wall, the roof extending over the at least one centralunit and the at least one modular unit.

In some embodiments, at least one of the at least one modular unit is aclean room.

In some embodiments, the at least one modular unit is configured forcell therapy operations.

According to another aspect of the present disclosure, a method ofassembling a facility for manufacturing at least one pharmaceuticalproduct includes providing at least one central unit; and providing atleast one modular unit in communication with the at least one centralunit such that the at least one central unit provides utilities to theat least one modular unit.

In some embodiments, the method includes providing a shell; positioningthe at least one central unit at least partially within the shell; andpositioning the at least one modular unit at least partially within theshell.

In some embodiments, the at least one modular unit includes at least oneof a fermentation unit, a pre-viral unit, a post-viral unit, a utilityspace, a warehouse, a media buffer facility, an office, a personnelunit, a production unit, a fill-finish unit, a dosage formulation unit,and a packaging unit.

In some embodiments, the at least one modular unit includes a pluralityof modular units arranged to maximize a number of modular units withinthe shell while minimizing a footprint of the shell.

In some embodiments, each modular unit of the plurality of modular unitsis directly adjacent at least one of the at least one central unit andanother one of the at least one modular unit.

In some embodiments, the at least one central unit and the plurality ofmodular units form a hub and spoke formation.

In some embodiments, the at least one central unit and the plurality ofmodular units are arranged in an H-shaped layout.

In some embodiments, the method includes one of supporting a bioreactoron a ground surface within the shell and supporting a bioreactor withinone of the at least one modular unit.

In some embodiments, an outer wall of the customizable facility is oneof: formed by the shell, the shell entirely enclosing the at least onecentral unit and the at least one modular unit; and formed by the shelland at least one of an outer wall of the at least one central unit andan outer wall of the at least one modular unit.

In some embodiments, the shell includes at least one side wall, the atleast one side wall encircling the at least one central unit and the atleast one modular unit, and a roof secured to an upper edge of the atleast one side wall, the roof extending over the at least one centralunit and the at least one modular unit.

In some embodiments, the at least one pharmaceutical product is abiosimilar product.

According to another aspect of the present disclosure, a campus forfabricating at least one pharmaceutical product includes a customizablefacility configured to manufacture the at least one pharmaceuticalproduct; a media/buffer plant configured to supply the customizablefacility with at least one processing material; and a utility buildingconnected by a utility line to at least one of the media/buffer plantand the customizable facility to provide at least one first utility viathe utility line.

In some embodiments, a warehouse is positioned adjacent the customizablefacility.

In some embodiments, the at least one first utility includes steamand/or an air supply.

In some embodiments, the customizable facility includes at least onecentral unit, and at least one modular unit in communication with the atleast one central unit such that the at least one central unit providesat least one second utility to the at least one modular unit.

In some embodiments, the customizable facility further includes a shell.The at least one central unit is positioned at least partially withinthe shell and the at least one modular unit is positioned at leastpartially within the shell.

In some embodiments, the at least one modular unit includes at least oneof a fermentation unit, a pre-viral unit, a post-viral unit, a utilityspace, a warehouse, a media buffer facility, an office, a personnelunit, a production unit, a fill-finish unit, a dosage formulation unit,and a packaging unit.

In some embodiments, a first utility of the at least one first utilityis the same as a second utility of the at least one second utility.

In some embodiments, a first utility of the at least one first utilityis different from a second utility of the at least one second utility.

In some embodiments, the at least one modular unit includes a pluralityof modular units arranged to maximize a number of modular units withinthe shell while minimizing a footprint of the shell.

In some embodiments, the media/buffer plant is positioned adjacent thecustomizable facility, and the utility building is positioned adjacentthe customizable facility.

In some embodiments, an outer wall of the customizable facility isformed by the shell, the shell entirely enclosing the at least onecentral unit and the at least one modular unit, or

In some embodiments, an outer wall of the customizable facility isformed by the shell and at least one of an outer wall of the at leastone central unit and an outer wall of the at least one modular unit.

In some embodiments, the shell includes at least one side wall thatencircles the at least one central unit and the at least one modularunit, and a roof secured to an upper edge of the at least one side wall,the roof extending over the at least one central unit and the at leastone modular unit.

In some embodiments, a first floor of the customizable facility includesa utilities area.

In some embodiments, the at least one pharmaceutical product is aplurality of pharmaceutical products, and the customizable facilityincludes a plurality of manufacturing wings, each manufacturing wingbeing configured to manufacture a respective pharmaceutical product ofthe plurality of pharmaceutical products.

In some embodiments, the campus includes a plurality of customizablefacilities.

In some embodiments, the campus includes at least one corridorconnecting the media/buffer plant to the customizable facility, the atleast one corridor being configured to allow a user to transport the atleast one processing material from the media/buffer plant to thecustomizable facility.

According to another aspect of the present disclosure, a method ofassembling a campus for manufacturing at least one pharmaceuticalproduct includes providing at least one customizable facility configuredto manufacture the at least one pharmaceutical product; providing amedia/buffer plant such that the media/buffer plant is configured tosupply the customizable facility with a processing material; andoperatively coupling a utility building to at least one of themedia/buffer plant and the customizable facility to provide at least onefirst utility to the media/buffer plant via a utility line.

In some embodiments, the method includes providing a warehouse adjacentthe customizable facility.

In some embodiments, the at least one first utility includes steamand/or an air supply.

In some embodiments, the method includes providing at least one centralunit, and providing at least one modular unit in communication with theat least one central unit such that the at least one central unitprovides at least one second utility to the at least one modular unit.

In some embodiments, the method includes providing a shell, positioningthe at least one central unit at least partially within the shell, andpositioning the at least one modular unit at least partially within theshell.

In some embodiments, the at least one modular unit includes at least oneof a fermentation unit, a pre-viral unit, a post-viral unit, a utilityspace, a warehouse, a media buffer facility, an office, a personnelunit, a production unit, a fill-finish unit, a dosage formulation unit,and a packaging unit.

In some embodiments, a first utility of the at least one first utilityis the same as a second utility of the at least one second utility.

In some embodiments, a first utility of the at least one first utilityis different from a second utility of the at least one second utility.

In some embodiments, the method includes providing the at least onemodular unit includes providing a plurality of modular units arranged tomaximize a number of modular units within the shell while minimizing afootprint of the shell.

In some embodiments, the method includes positioning the media/bufferplant adjacent the customizable facility, and positioning the utilitybuilding adjacent the customizable facility.

In some embodiments, an outer wall of the customizable facility isformed by the shell, the shell entirely enclosing the at least onecentral unit and the at least one modular unit.

In some embodiments, an outer wall of the customizable facility isformed by the shell and at least one of an outer wall of the at leastone central unit and an outer wall of the at least one modular unit.

In some embodiments, the shell includes at least one side wall, the atleast one side wall encircling the at least one central unit and the atleast one modular unit, and a roof secured to an upper edge of the atleast one side wall, the roof extending over the at least one centralunit and the at least one modular unit.

According to another aspect of the present disclosure, a method ofmanaging a pharmaceutical facility includes providing a campus forfabricating at least one pharmaceutical product, the campus including atleast one customizable facility configured to manufacture the at leastone pharmaceutical product, a media/buffer plant, and a utility buildingconnected by a utility line to at least one of the media/buffer plantand the at least one customizable facility to provide at least one firstutility via the utility line; and offering at least a portion of thecampus to a customer desiring to manufacture a pharmaceutical product.

In some embodiments, the at least the portion of the campus includes amanufacturing wing in the at least one customizable facility.

In some embodiments, the step of offering at least the portion of thecampus includes offering an option to buy the at least the portion ofthe campus.

In some embodiments, the step of offering at least the portion of thecampus includes offering an option to lease the at least the portion ofthe campus.

According to another aspect of the present disclosure, a method ofadjusting a capacity of a pharmaceutical facility includes providing acampus for fabricating at least one pharmaceutical product, the campusincluding at least one customizable facility configured to manufacturethe at least one pharmaceutical product, a media/buffer plant, and autility building connected by a utility line to the media/buffer plantto provide at least one first utility via the utility line; offering afirst portion of the campus to a first customer desiring to manufacturea first pharmaceutical product; and constructing a second portion of thecampus for manufacturing a second pharmaceutical product, the secondportion of the campus being technology agnostic.

In some embodiments, the second pharmaceutical product is one of:different from the first pharmaceutical product and identical to thefirst pharmaceutical product.

In some embodiments, the first portion of the campus is a manufacturingmodule within the customizable facility.

In some embodiments, the method includes offering the second portion ofthe campus to a second customer; and constructing a third portion of thecampus for manufacturing a third pharmaceutical product, the thirdportion being technology agnostic.

In some embodiments, the first portion is accessible only via a firstdedicated access route that is accessible by the first customer, butthat is not accessible by the second customer; and the second portion isaccessible only via a second dedicated access route that is accessibleby the second customer, but that is not accessible by the firstcustomer.

In some embodiments, the method includes continually maintaining atechnology agnostic portion of the campus in a ready state for a newcustomer to begin manufacturing a pharmaceutical.

DESCRIPTION OF THE FIGURES

The accompanying drawings are not intended to be drawn to scale. Forpurposes of clarity, not every component may be labeled in everydrawing. In the drawings:

FIG. 1 is a top view of an embodiment of a customizable facilityaccording to the present disclosure;

FIG. 2A is a perspective view of the embodiment of FIG. 1;

FIG. 2B is a perspective view of the embodiment of FIG. 1, showing alocation of a component within the customizable facility;

FIG. 2C is a perspective view of the embodiment of FIG. 1, showing alocation of another component within the customizable facility;

FIG. 2D is a perspective view of the embodiment of FIG. 1, showing alocation of another component within the customizable facility;

FIG. 2E is a perspective view of the embodiment of FIG. 1, showing alocation of another component within the customizable facility;

FIG. 3A is an exploded view of an embodiment of a modular unit accordingto the present disclosure;

FIG. 3B is an exploded view of another embodiment of a modular unitaccording to the present disclosure;

FIG. 3C is an exploded view of another embodiment of a modular unitaccording to the present disclosure;

FIG. 3D is an exploded view of another embodiment of a modular unitaccording to the present disclosure;

FIG. 3E is an exploded view of another embodiment of a modular unitaccording to the present disclosure;

FIG. 4 is a front perspective cutaway view of an embodiment of acustomizable facility according to the present disclosure;

FIG. 5 is a perspective view of a set of modular units and a centralunit arranged in an H-shaped layout;

FIG. 6 is a top view of a set of modular units and a central unitarranged in an H-shaped layout;

FIG. 7 is a perspective view thereof;

FIG. 8 is a top view of modular units and central units arranged inanother arrangement within a shell;

FIG. 9 is a top view of another arrangement of modular units and centralunits arranged within a shell;

FIG. 10 is a top view of another arrangement of modular units andcentral units;

FIG. 11 is a schematic view of a set of modular units and a central unitarranged in a spine;

FIG. 12 is a perspective view of an embodiment of a campus according tothe present disclosure;

FIG. 13 is an enlarged perspective view of a portion of the campus shownin FIG. 12;

FIG. 14 is another perspective view of the embodiment of the campus ofFIG. 12; and

FIG. 15 is a cutaway perspective view of another embodiment of acustomizable facility according to the present disclosure.

DETAILED DESCRIPTION

The structures disclosed herein for a customizable facility are usefulfor manufacturing at least one product at a given time. The structuresdisclosed herein are particularly useful for manufacturing a variety ofproducts that utilize common resources.

The present disclosure provides systems and methods that allow for oneor more scalable product lines to be at least partially enclosed withina shell of a customizable facility. Because the structure is adaptable,it does not require a user to commit the structure to a single productline for a long period of time. The structure can be reconfigured tomeet the dimensional requirements of a product line.

The customizable facility of the present disclosure enables a user todecrease construction timelines, reduce capital expenditures, increaseglobal design standardization, and to comply with various standardsaround the globe.

The customizable structure allows for shorter turnaround times fromconception to construction, allows for decreased construction sitecongestion and requires fewer fixed assets when implementing a newproduct line.

Generally, the customizable facility comprises a shell, at least onecentral unit positioned within the shell, and at least one modular unit,each modular unit being positioned within the shell.

FIG. 1 is a top plan view of an exemplary embodiment of a customizablefacility generally indicated at 10. The customizable facility of FIG. 1can be constructed in a series of phases, such as a first phase 12, asecond phase 14, and subsequent phases.

The features installed in the first phase 12 of construction of thecustomizable facility 10 of FIG. 1 include an air controlled entryway16, a changing area 18, a utilities area 20, a first manufacturing wing22A, a first office space 24A, and at least one corridor 28 allowingoccupants of the customizable facility 10 to move within thecustomizable facility 10 from one area to another.

Outside of the customizable facility 10, there is a yard 30 thatincludes a handling area 32 for handling equipment and materials. Theyard area 30 is shown adjacent to a roadway 34. Generally, thecustomizable facility 10 can be expanded in any direction. Additionally,the customizable facility 10 is constructed such that it can expand in aseries of construction phases and/or sub-phases within the physicalconstraints of the surrounding features, such as the yard area 30 andthe roadway 34.

FIG. 1 shows additional features that can be added during a second phase14 of construction, such as a second manufacturing wing 22B and a secondoffice space 24B.

The layout of the customizable facility 10 can be configured formanufacturing in clean room settings. The customizable facility 10utilizes a hybrid stick or frame build building and modular buildingswith a utilities unit (or utility hub).

Referring now to FIGS. 2A-2E, the relative positions of variouscomponents of the customizable facility are shown.

FIG. 2A shows a perspective view of the exterior walls of the outershell 36 of the customizable facility 10. The outer shell (or shell) 36at least partially encloses a central unit (which may be a centralutilities unit) 38 and at least partially encloses a plurality ofmodular units 40, as discussed further below. In some embodiments, theouter shell 36 entirely encloses the utilities unit (which may be acentral utilities unit) 38 and entirely encloses the plurality ofmodular units 40.

The outer shell 36 can be constructed according to traditional stickbuilding or another method, such as, but not limited to, prefabricatedmodules. For example, the outer shell 36 can be fabricated from a steelstructure using traditional building methods. The outer shell 36 can besupported on footings secured in the ground. The outer shell 36 isweatherproof.

The outer shell 36 forms a superstructure. In some embodiments, theouter shell 36 can be a “Butler” style building, which is known in theart of building construction.

The outer shell 36 includes side walls 42 that are dimensioned andconfigured to encircle one or more central units 38 and one or moremodular units 40 included in the customizable facility 10, and describedin more detail below.

A roof 44 is secured to upper edges of the side walls 42, with the roof44 extending over the central unit(s) 38 and the modular unit(s) 40.Thus, the side walls 42 and the roof 44 enclose the central unit(s) 38and the modular unit(s) 40, which are positioned within the shell 36.The central unit(s) 38 and the modular unit(s) 40 may be supported on afloor of the shell 36 or on another support surface on which the shellis secured. The customizable facility 10 provides a partially-modular(what could be called a modular stick build) method that includes abasic superstructure that is then filled in with modular type elements.

In one embodiment, the customizable facility 10 of FIG. 2A has an outerheight of 30 meters. In one embodiment, each manufacturing wing has alength of 100 meters and a width of 30 meters.

FIG. 2B shows the exterior of the customizable facility 10 in brokenlines, with the utilities area in solid lines. The utilities area 20 caninclude a central unit (which may be referred to as a Central UtilityBay (CUB) or utilities building or central utility module) 38 that ispositioned towards the middle of the customizable facility 10.

The shell 36 of FIG. 1 also encloses a future utilities area 46, whichis fully occupied by a future utilities module in FIG. 1. The futureutilities area 46 is adjacent to the utilities module 38, and is shownin FIG. 1. The future utilities area 46 can be used as a warehouse areaadjacent to the utilities module 38. The future utilities area 46 withinthis customizable facility 10 could also suite high bay applications,such as a 40 foot tall warehouse having an automated search andretrieval system (ASARS).

In some embodiments, the utilities module 38 and the future utilitiesarea 46 are a single utilities module, which is divided into a utilitiessection and a future utilities section.

The central utility module 38 does not need to be at the center of thecustomizable facility 10. The central utility module 38 can bepositioned along an outer edge of the customizable facility 10 in someembodiments.

FIG. 2C shows the exterior of the customizable facility 10 in brokenlines, with the manufacturing wings 22A, 22B in solid lines.

The manufacturing wings 22A, 22B are configured to contain modular units40 for a product line, such as fermentation modules or purificationmodules. The customizable facility 10 is easily expandable and scalable,and the different modular units 40 within the manufacturing wings 22A,22B can be used to produce completely different products in the samecustomizable facility 10.

For example, in a modular unit 40 configured as a first fermentationmodule, a user could be manufacturing one type of product, such as amonoclonal antibody product derived from a mammalian cell line. In asecond modular unit 40, the user could manufacture a completelydifferent product, such as a microbial product. The customizablefacility 10 of the present disclosure is capable of supporting multipleproduct lines simultaneously and multiple customers from a single,expandable superstructure. The customizable facility 10 of the presentdisclosure is capable of being expanded to add additional product lines.

Reactors can be supported within the modular units 40 of themanufacturing wings 22A, 22B of the customizable facility 10. Thecustomizable facility 10 can support any desired and suitable vesselvolume. For example, in some aspects such as that shown in FIG. 1, thecustomizable facility 10 can be configured to contain up to 20,000 literproduction vessels, and storage vessels (e.g., harvest) in excess of20,000 liters (e.g., 23,000-24,000 liters). For example, thecustomizable facility 10 can be dimensioned and configured to supportvessels having a volume of about 20,000 liters, 15,000 liters, 10,000liters, 5,000 liters, 2,000 liters and/or 1,000 liters. Vessels havingother volumes can also be supported.

Any typical manufacturing and clean room equipment can be included inthe customizable facility 10, and the customizable facility 10 can befully suitable for cGMP (current good manufacturing practice) processes.

Examples of some equipment that can be fit in the customizable facility10 include, but are not limited to: bioreactor, disc stack centrifuge,tangential flow filtration (TFF) skid, depth filtration skid, in-linedilution skid, chromatography columns with associated control equipment,media tank, harvest tank, purification vessels, depth filter holders,water softening and dechlorination system, clean steam generator, waterfor injection (WFI) storage tank, WFI break tank, WFI still, coolingtowers, switchboard, emergency generator, chiller, hydronic pumps,autoclave, air handling units, process waste neutralization (such as afiberglass reinforced plastic (FRP)), biowaste collection andinactivation system, clean-in-place systems, glass washer, and/or otherequipment.

Bioreactors in the customizable facility 10 of the present disclosurecan be ground based reactors. Alternatively, the bioreactors could besuspended from the structure itself. For example, the bioreactors couldbe suspended from one or more of the modular units 40.

The customizable facility 10 can include one or more central unit 38 andone or more modular unit 40. In some embodiments, each modular unit 40is selected from the group of: a fermentation or cell culture unit, apre-viral unit, a post-viral unit, a utility yard, a warehouse, a mediabuffer facility, an office, a personnel unit, a production unit, afill-finish unit, a dosage formulation unit, and a packaging unit. Aproduction unit is useful for manufacturing a product. A fill-finishunit is useful for filling a container such as a vial. A dosageformulation unit dispenses a set dose of a product. A packaging unitpackages a product for distribution or sale.

The space allocated for each modular unit can be divided further asneeded to fit specific processing requirements. Each manufacturing wing22A, 22B can be configured to allow more than one modular unit 40 to bepositioned within the respective manufacturing wing 22A, 22B.

In FIG. 1 and FIG. 2C, a first manufacturing wing 22A comprises threemodular units 40. A second manufacturing wing 22B comprises two modularunits 40. The central utilities area 20 has a length of 50 meters and awidth of 20 meters, and has three internal levels. The central utilitiesblock is expandable.

In some embodiments, at least one of the modular units 40 is a cleanroom. In some embodiments, at least one of the modular units 40 includesa clean room section within the respective modular unit 40.

The building shell 36 is designed to accommodate different productionmodules. In some embodiments, the shell can house four 20,000 litervessels for a mammalian cell line. In some embodiments, the shell canhouse four 2,000 liter vessels for single-use technology operations.

In some embodiments, a manufacturing wing can include a modular unitcontaining four 20,000 liter vessels and downstream processing equipmentand configured for manufacturing a monoclonal antibody product derivedfrom a mammalian cell line, a modular unit containing single-useequipment for manufacturing a monoclonal antibody product derived from amammalian cell line having four 20,000 liter vessels, a modular unitconfigured for manufacturing a microbial product, and/or a modular unitcontaining single-use equipment for manufacturing a microbial product.

In one embodiment, a modular unit is configured for mammalianmanufacturing and includes four 20,000 liter vessels and downstreamprocessing equipment. In another embodiment, a modular unit includesfour 20,000 liter vessels for commercial and clinical production. Inanother embodiment, a modular unit includes one 1,000 liter vessel forclinical production. In another embodiment, a modular unit is configuredfor manufacturing a microbial product, and includes one 15,000 litervessel. In another embodiment, a modular unit includes three 5,000 litervessels. In another embodiment, a modular unit includes one or moreprocess development labs. In another embodiment, a modular unit includesfill and finish clinical development vial fill equipment, one or moreset of lyophilizing equipment, equipment for manufacturing pre-filledsyringes, and/or equipment for manufacturing high potency products forcommercial applications. In some embodiments, a modular unit includescell therapy equipment. In some embodiments, a modular unit includesviral therapy equipment.

FIG. 2D shows the exterior of the customizable facility 10 in brokenlines, with the first office space 24A and the second office space 24Bin solid lines. The first office space 24A includes offices, lockers forpersonal storage, and a support area. The second office space 24Bincludes offices, lockers for personal storage, and a support area. Thefront wall 48A of the first office space 24A forms a portion of thefront outer surface of the customizable facility 10, as shown in FIG.2A. The front wall 48B of the first office space 24B forms a portion ofthe front outer surface of the customizable facility 10. Thus, eachoffice space 24A, 24B is only partially enclosed by the shell 36 of thecustomizable facility 10.

Similarly, in some embodiments, an outer wall of the central unit and/oran outer wall of one of the at least one modular units forms at least apart of the outer wall of the customizable facility. In someembodiments, an upper surface of a central utility module and/or anupper surface of a modular unit forms part of an upper surface of thecustomizable facility.

FIG. 2E shows the exterior of the customizable facility 10 in brokenlines, with the changing area 18 in solid lines. The changing area 18allows users to enter the customizable facility 10 and change fromstreet clothes into work clothes. The changing area 18 in FIG. 2E isfurther subdivided into a male changing area 18A and a female changingarea 18B. In some embodiments, the changing area 18 is subdivided intotwo or more changing areas. In some embodiments, the changing area 18 isnot subdivided.

In other embodiments, the relative positions of the first manufacturingwing 22A and second manufacturing wings 22B, the first office space 24A,the second office space 24B, the changing area 18, and the utilitiesarea 20 can be positioned differently in the customizable facility 10and/or oriented differently with respect to the customizable facility10.

Scaffolding and corridors 28 allow users of the customizable facility 10to access the utilities unit 38 of the utilities area 20 and the modularunits (fermentation, etc. modules) 40.

After adding the second phase 14 of construction to the customizablefacility 10, over time a user may wish to further expand thecustomizable facility 10. For example, consumers in the global economymay develop increased demand for a product that the user ismanufacturing, or consumers in the global economy may develop increaseddemand for a product that the user could produce. To respond to suchincreases in demand for a product, the user can expand the customizablefacility 10 in subsequent phases of construction that add additionalfeatures to the customizable facility of FIG. 1. In some embodiments,such additional features (such as additional modular units, anadditional manufacturing wing, or another component of a customizablefacility) are positioned horizontally adjacent to the firstmanufacturing wing 22A or the second manufacturing wing 22B. In someembodiments, such additional features are positioned vertically adjacentto the first manufacturing wing 22A and/or the second manufacturing wing22B.

Referring now to FIGS. 3A-3E, it is possible for a user to expand amanufacturing wing, such as the first manufacturing wing 22A or thesecond manufacturing wing 22B of FIG. 1, in different sub-phases. A usercould convert a manufacturing wing layout from one of the configurationsshown in FIGS. 3A-3E to another configuration shown in FIGS. 3A-3E.Alternatively, a user could convert a manufacturing wing layout toanother configuration.

FIG. 3A shows a partially exploded view of an embodiment of a modularunit 40A that is configured as a fill finish module. The fill finishmodule of FIG. 3A has a single floor 60A with a footprint of 1,500square meters. The fill finish module includes a mezzanine for an HVACplant room and some localized utilities. A free field 50A is shown inbroken lines adjacent to the fill finish module, and has a footprint of1,500 square meters. The free field 50A can be used for a variety ofpurposes, such as product storage. Together, the fill finish module 40Aand the free field 50A extend over the 3,000 square meter footprint ofthe second manufacturing wing 22B.

FIG. 3B shows a partially exploded view of an embodiment of a modularunit 40B that is configured as a “2 k module.” The 2 k module of FIG. 3Bhas a single floor 60B with a footprint of 1,500 square meters. The 2 kmodule can enclose a 2,000 liter vessel. The 2 k module includes amezzanine for an HVAC plant room and some localized utilities. A freefield 50B is shown in broken lines adjacent to the 2 k module, and has afootprint of 1,500 square meters. The free field 50B can be used for avariety of purposes, such as product storage. Together, the 2 k module40B and the free field 50B extend over the 3,000 square meter footprintof the second manufacturing wing 22B.

FIG. 3C shows a partially exploded view of an embodiment of a modularunit 40C that is configured as “a 5 k module.” The 5 k module of FIG. 3Chas a single floor 60C with a footprint of 3,000 square meters. The 5 kmodule can enclose a 5,000 liter vessel. The 5 k module includes amezzanine for an HVAC plant room and some localized utilities. The 5 kmodule extends over the 3,000 square meter footprint of themanufacturing wing.

FIG. 3D shows a partially exploded view of an embodiment of a modularunit 40D that is configured as a “15 k module.” The 15 k module of FIG.3D has a first floor 60D and a second floor 62. The 15 k module of FIG.3D has a footprint of 3,000 square meters. The 15 k module can enclose a15,000 liter vessel. The 15 k module includes a local HVAC unit, a cleanin place (CIP) unit, and a temperature control unit (TCU). Thetemperature control unit in some embodiments includes water jackets withheat exchangers on a tank to control the temperature of a tank used in aproduct line. A CIP unit is typically a modular skid and has severaltanks to hold a cleaning solution (such as caustic solutions andbleach), pumps, and sensors to send the cleaning solution to theappropriate tank to be cleaned.

The first floor 60D of the 15 k module extends over the 3,000 squaremeter footprint of the manufacturing wing. The second floor 62 of the 15k module extends vertically above the first floor of the 15 k module,and extends above the 3,000 square meter footprint of the manufacturingwing. Together, the first floor 60D of the 15 k module and the secondfloor 62 of the 15 k module have a combined area of 6,000 square meters.

FIG. 3E shows a partially exploded view of an embodiment of a modularunit 40E that is configured as a “20 k module.” The 20 k module of FIG.3E has a footprint of 3,000 square meters. The 20 k module can enclose a20,000 liter vessel. The 20 k module includes a local HVAC unit, a CIPunit, and a TCU. The 20 k module includes a first floor, a second floor,and a third floor. The first floor 60E of the 20k module extends overthe 3,000 square meter footprint of the manufacturing wing. The secondfloor 64 of the 20 k module extends vertically above the first floor 60Eof the 20 k module, and extends above the 3,000 square meter footprintof the manufacturing wing. The third floor 66 of the 20 k module extendsvertically above the first floor 60E of the 20 k module and the secondfloor 64 of the 20 k module, and extends above the 3,000 square meterfootprint of the manufacturing wing. Together, the first floor 60E ofthe 20 k module, the second floor 64 of the 20 k module, and the thirdfloor 66 of the 20 k module have a combined area of 9,000 square meters.

FIG. 4 is a front perspective cutaway view of an exemplary embodiment ofa customizable facility generally indicated at 110 according to thepresent disclosure. The customizable facility 110 layout can beconfigured for manufacturing in clean room settings. The customizablefacility 110 utilizes a hybrid stick or frame build building and modularbuildings with a centrally located utility hub (or central unit) 114.

An outer shell (or shell) 112 encloses a central unit 114 and aplurality of modular units 116 adjacent to the central unit 114. Theouter shell 112 can be constructed according to traditional stickbuilding or another method, such as, but not limited to, prefabricatedmodules. For example, the outer shell 112 can be fabricated from a steelstructure using traditional building methods. The outer shell 112 can besupported on footings secured in the ground. The outer shell 112 isweatherproof.

The outer shell 112 forms a superstructure. In some embodiments, theouter shell 112 can be a “Butler” style building, which is known in theart of building construction.

The shell 112 includes side walls 118 that are dimensioned andconfigured to encircle one or more central units 114 and one or moremodular units 116 included in the customizable facility 110, anddescribed in more detail below. A roof 120 is secured to upper edges ofthe side walls 118, with the roof 120 extending over the central unit(s)114 and the modular unit(s) 116. Thus, the side walls 118 and the roof120 enclose the central unit(s) 114 and the modular unit(s) 116, whichare positioned within the shell 112. The central unit(s) 114 and themodular unit(s) 116 may be supported on a floor 122 of the shell 112 oron another support surface on which the shell 112 is secured. Thecustomizable facility 110 provides a partially-modular (what could becalled a modular stick build) method that includes a basicsuperstructure that is then filled in with modular type elements.

Within the shell 112, the customizable facility 110 of FIG. 4 includesat least one central unit 114, which each may be referred to as aCentral Utility Bay (CUB). The central unit 114 provides centralutilities in FIG. 4. As shown, the CUB 114 is in the middle of thestructure with modular units 116, which may be referred to asmanufacturing pods, which stem from the CUB 114 (or from a plurality ofCUBs). In FIG. 4, the modular units 116 are fermentation modules. Thecustomizable facility 110 is easily expandable and scalable, and thepod/modular approach (i.e., a hub and spoke type approach) allows thedifferent modules to produce completely different products in the samecustomizable facility 110.

For example, in a first fermentation module, such as the fermentationmodule on the left of FIG. 4, a user could be manufacturing one type ofproduct, such as a monoclonal antibody product derived from a mammaliancell line. In a second module, such as the fermentation module on theright of FIG. 4, the user could manufacture a completely differentproduct, such as a microbial product. The customizable facility 110 ofthe present disclosure is capable of supporting multiple product linessimultaneously and multiple customers from a single, expandablesuperstructure.

FIG. 4 shows reactors 124 supported within the customizable facility110. The customizable facility 110 can support any desired and suitablevessel volume. For example, in some aspects such as that shown in FIG.4, the facility 110 can be configured to contain up to 20,000 Literproduction vessels, and storage vessels (e.g., harvest) in excess of20,000 liters (e.g., 23,000-24,000 liters). For example, thecustomizable facility 110 can be dimensioned and configured to supportvessels 124 having a volume of about 20,000 liters, 15,000 liters,10,000 liters, 5,000 liters, 2,000 liters and/or 1,000 liters. Vessels124 having other volumes can also be supported.

Scaffolding 126 and corridors 128 allow users of the facility 110 toaccess the central unit (central utility) 114 and the modular units(fermentation, etc. modules) 116. As shown in FIG. 4, the scaffolding126 is positioned within the shell 112.

In some embodiments, one or more central units (CUBs) 114 and the one ormore modular units 116 are arranged in a hub and spoke arrangement.

Any typical manufacturing and clean room equipment can be included inthe customizable facility 110, and the customizable facility 110 can befully suitable for cGMP processes.

Examples of some equipment that can be fit in the facility 110 include,but are not limited to: bioreactor, disc stack centrifuge, tangentialflow filtration (TFF) skid, depth filtration skid, in-line dilutionskid, chromatography columns with associated control equipment, mediatank, harvest tank, purification vessels, depth filter holders, watersoftening and dechlorination system, clean steam generator, water forinjection (WFI) storage tank, WFI break tank, WFI still, cooling towers,switchboard, emergency generator, chiller, hydronic pumps, autoclave,air handling units, process waste neutralization (such as a fiberglassreinforced plastic (FRP)), biowaste collection and inactivation system,clean-in-place systems, glass washer, and/or other equipment.

Bioreactors in the customizable facility 110 of the present disclosurecan have ground based reactors 124 as is shown in FIG. 4. Alternatively,the bioreactors 124 could be suspended from the structure itself. Forexample, the bioreactors 124 could be suspended from one or more of themodular units 116.

The shell 112 of FIG. 4 encloses a warehouse area 130 towards the backright of the facility 110. The warehouse area 130 within this facility110 could also suite high bay applications, such as a 40 foot tallwarehouse having an automated search and retrieval system (ASARS).

The customizable facility 110 can include one or more central unit 114and one or more modular unit 116. In some embodiments, each modular unit116 is selected from the group of: a fermentation or cell culture unit,a pre-viral unit, a post-viral unit, a utility yard, a warehouse, amedia buffer facility, an office, a personnel unit, a production unit, afill-finish unit, a dosage formulation unit, and a packaging unit. Thespace allocated for each modular unit can be divided further as neededto fit specific processing requirements.

In some embodiments, at least one of the modular unit(s) 116 is a cleanroom.

FIG. 5 shows a perspective view of a set of a central unit 114 andmodular units 116 arranged in an H-shaped layout 132. The position ofeach modular unit 116 can be adjusted to best fit processingrequirements.

FIGS. 6 and 7 show an embodiment of a customizable facility in which acentral unit 114 and a set of eight modular units, configured aspurification units 116A and fermentation units 116B, are arranged in anH-shaped layout 133 when viewed from above. The shell 112 is not shownin these views. The plan view of FIG. 6 shows a central unit (labeled asa central utilities building) 114 having a first row of modular units,configured as purification units 116A and fermentation units 116B,arranged in a linear array 134 adjacent to a first side 136 of thecentral unit 114, and a second row of modular units, configured aspurification units 116A and fermentation units 116B, arranged in alinear array 138 adjacent to a second side 140 of the central unit 114.The array 134 of modular units includes four modular units, with a firstpurification unit 116A at a first end of the array 134, two fermentationunits 116B at the middle of the array 134, and a second purificationunit 116A at a second end of the array 134. Similarly, the array 138 ofmodular units includes four modular units, with a first purificationunit 116A at a first end of the array 138, two fermentation units 116Bat the middle of the array 138, and a second purification unit 116A at asecond end of the array 138.

The two fermentation units 116B of the first array 134 of modular unitseach include a side wall that is in direct facing engagement with afirst side wall 136 of the central unit 114. Similarly, the twofermentation units 116B of the second array 138 of modular units eachinclude a side wall that is in direct facing engagement with a secondside wall 140 of the central unit 114. The purification units 116A arein direct facing relation with their respectively adjacent fermentationunits 116B. Because of the direct facing engagement of the central unit114 and the fermentation units 116B, the number of central units 114 andmodular units that can fit within a shell 112 of a given size isincreased. Likewise, the footprint of a shell 112 required to enclose agiven set of central units 114 and modular units is decreased.Optionally, in some aspects the side walls of the fermentation units116B(or other modular units) need not be in direct facing engagement butcould be spaced so as to provide any desired footprint.

The modular unit(s) 116 and the central unit(s) 114 can be arranged tofacilitate manufacture of a plurality of products simultaneously. Themodular unit(s) 116 and central unit(s) 114 are arranged to efficientlyshare resources between the manufacturing lines of the respectiveproducts. For example, in some embodiments, the central unit 114contains at least one of: a power generator, plumbing lines, powerlines, and other resources that can be shared by the modular units 116.Additionally, the modular unit(s) 116 and the central unit(s) 114 can bearranged to facilitate future expansion of manufacturing capacity. Forexample, a single modular unit 116 can be utilized initially, withability to add additional modular units 116 at a later time with minimalimpact to existing operations.

In some embodiments, each of the modular units 116 includes its ownrespective heating, ventilation, and air conditioning (HVAC) system, asrequired for operation and segregation.

In some embodiments, the hub and spoke arrangement can resemble theletter H, such as in the plan view of FIG. 6. In other embodiments, thehub and spoke arrangement does not resemble the letter H. Other shapesare possible, including but not limited to: a square, a rectangle, apentagon, and other geometric shapes, so long as it has a central unit(a central utility bay) with at least one modular unit extending fromthere. Additional shapes are possible, for example, as shown in FIG. 10.In some embodiments, for example, a linear “spine” shape can be used oran “E” shape can be used such that the hub and spoke arrangementresembles the letter E.

In some embodiments, the central unit 114 is not at the center of thearrangement of the central unit 114 and the modular units 116. Thearrangement of the modular units 116 and the central unit 114 ispreferably configured to reduce the number of modular units 116 requiredfor a given set of manufacturing lines.

The modular units 116 can be segmented off from each other to reducecross-contamination of product or suites.

FIG. 8 shows a plan view of another preferred embodiment of thecustomizable facility 1000 of the present disclosure. Two central units114 are located towards the bottom center of the plan view of thestructure shown in FIG. 8, and are positioned between shared corridors128 that extend alongside walls of the central units 114. To the left ofthe central units 114 is a grouping of six modular units. This groupingincludes two pre-viral units 116C, two post-viral units 116D, and twofermentation units 116B. To the right of the central units 114 as shownin FIG. 8 is a grouping of six modular units, including two pre-viralunits 116C, two post-viral units 116D, and two fermentation units 116B.This configuration is designed to expand additional capability as needed(e.g., see FIG. 10 as example of an embodiment showing expansionoptions). Along the top of the facility 1000 as shown in FIG. 8, thereare other modular units, including a utility yard unit 116E, twowarehouse units 116F, two media/buffer facility units 116G, and officeunit 116H, and two personnel access units 116J. Not shown in this figureis the capability to add independent buffer hold modular units directlyabove each purification unit. Shared corridors 128 extend along walls ofthe units, so that users can access each of the modular units of FIG. 8and the central units 114 from a common corridor 128.

The different units can have different classification levels based ongrading standards. For example, different units can have differentclassification levels based on grading standards set by the UnitedStates Food and Drug Administration or grading standards set byEudraLex, The Rules Governing Medicinal Products in the European UnionVolume 4 EU Guidelines to Good Manufacturing Practice Medicinal Productsfor Human and Veterinary Use, supplemented by Annex 1 Manufacture ofSterile Medicinal Products in the European Union. For example, thepre-viral units 116C, the post-viral units 116D, and the media/bufferfacility units 116G in FIG. 8 are classified as “Grade C,” while thefermentation units 116B are classified as “Grade D,” according to theEuropean Union standards, and the remaining units are unclassified.Other classifications for the units are possible, and can be selectedaccording to user needs.

FIG. 9 shows another embodiment of a customizable facility 1200 of thepresent disclosure. FIG. 9 includes a central unit (a central utilitiesbuilding) 114 having corridors 128 for clean material and personnel oneither side of the central unit 114. The corridors 128 extend from awarehouse 116F at an upper end of the facility 1200 shown in FIG. 9 andextend beyond the central unit 114 at the bottom of the facility. Onouter sides of the respective corridors 128 are locker room units 116K,pre-viral units 116C, post-viral units 116D, and fermentation units116B.

In an embodiment such as the one shown in FIG. 9, the fermentation units116B each have dimensions of 63 feet by 65 feet, and are 35 feet high.In an embodiment such as the one shown in FIG. 9, the pre-viral units116C may have dimensions of 62 feet by 50 feet, and are 17 feet high. Inan embodiment such as the one shown in FIG. 9, the post-viral units 116Deach have dimensions of 62 feet by 65 feet, and are 35 feet high. Inother embodiments, the units may have other dimensions.

FIG. 10 shows another embodiment of a customizable facility 1300 of thepresent disclosure, with the shell 112 not shown. FIG. 10 includes fiverows of zones. A first row (a top row) 142 in the plan view of FIG. 10includes purification zones 117A. A second row 144 includes fermentationzones 117B. A third row 150 includes a central utilities zone 114. Afourth row 146 includes fermentation zones 117B. A fifth row 148includes purification zones 117A.

In some aspects, a customizable facility for manufacturing at least onepharmaceutical product may include at least one central unit and atleast one modular unit, but the customizable facility does not include ashell. Each modular unit is in communication with the at least onecentral unit such that the at least one central unit provides utilitiesto each modular unit.

The zones in solid lines indicate a set of zones that may be provided inan initial configuration. In this initial configuration 160, there arethree purification zones (PURE 1, PURE 3, PURE 5) 117A in the first row142, three fermentation zones (FERM 1, FERM 3, FERM 5) 117B in thesecond row 144, a central utilities zone (CENTRAL UTILITIES 1) 115 inthe third row 150, three fermentation zones (FERM 2, FERM 4, FERM 6)117B in the fourth row 146, and three purification zones (PURE 2, PURE4, PURE 6) 117A in the fifth row 148.

A set of zones 162 could be added by extending an array of zones to theright. For example, two additional purification zones (PURE 7, PURE 9)117A could be added to the first row 142, two additional fermentationzones (FERM 7, FERM 9) 117B could be added to the second row 144;additional central utilities zones 114 could be added to the third row150, two additional fermentation zones (FERM 8, FERM 10) 117B could beadded to the fourth row 146, and two additional purification zones (PURE8, PURE 10) 117A could be added to the fifth row 148. Arrows to theright, such as the arrow A between the fermentation zones 117B labeledFERM 9 and FERM N+1, indicate the direction of potential expansion ofthe arrangement of zones. Additional zones could be added to therespective rows as needed, and FIG. 10 shows a purification unit (PUREN+1) 117A at the end of the first row 142, a fermentation zone (FERMN+1) 117B at the end of the second row 144, a fermentation zone (FERM N)117B along the direction of arrow B at the end of the fourth row 146,and a purification zone (PURE N) 117A at the end of the fifth row 148.The value of N can be an integer value selected by a user as needed, andis limited only by the internal dimensions of the shell 112 within whichthe modular units 116 and central unit(s) 114 are positioned.

The third row can be expanded by adding central utilities zones 114 tothe third row 150 along an arrow C.

The zones of FIG. 10 are regions in that could each be a central unit ora modular unit (e.g., a fermentation unit, a purification unit, etc.),or regions that could support equipment for a unit. Where FIG. 10 showsa zone (such as zone FERM 1), this zone can be subdivided into afermentation unit FERM 1 and one or more hallways within the zone. In atleast some zones, a unit can occupy the entire zone.

Modular units 116 disclosed herein may be further subdivided intosub-units. For example, a unit could have a pre-viral sub-unit and apost-viral sub-unit. The post-viral sub-unit is virus-free.

In relation to FIGS. 4-9, although the figures show views that aredivided into regions that are described as units, the regions of theviews can designate zones (such as a purification zone, a fermentationzone, etc.), which each include a unit and one or more hallways forconnecting units.

FIG. 11 illustrates another example embodiment of a facility 1400 inwhich a central unit 114 is in the shape of a linear “spine” with aplurality of modules 116 emanating from the spine. In this embodiment,the modules 116 can be added subsequently in multiple constructionphases such that the facility is expanded over time.

According to an aspect of the present disclosure, a method of assemblinga facility for manufacturing at least one pharmaceutical product mayinclude providing a shell, positioning at least one central unit atleast partially within the shell, and positioning at least one modularunit at least partially within the shell.

According to an aspect of the present disclosure, a campus forfabricating at least one pharmaceutical product is provided. Oneembodiment of a campus 1500 is shown in FIGS. 12 and 13. The campus 1500includes five customizable facilities, each indicated at 1510. Eachcustomizable facility 1510 is configured to manufacture at least onepharmaceutical product. The five customizable facilities 1510 rely onthe existing infrastructure and support network provided by the campus.For example, media can be provided to the customizable facilities 1510from a media/buffer plant (media/buffer facility) 1520 positioned nearthe customizable facilities 1510. In FIG. 12, the media/buffer plant1520 is adjacent four of the customizable facilities 1510.

In some aspects, the media/buffer plant 1520 is operatively coupledand/or configured to provide or supply the at least one customizablefacility 1510 with a processing material, such as but not limited tomedia or buffer. In some aspects, the media/buffer plant 1520 may beconfigured to provide the processing material in a transportablecontainer, such as a bag, and transport the processing material to thecustomizable facility 1510 via truck, rail, or other ground transportsystem on the campus. In some aspects, the campus can include a supplyline 1530, with the respective supply line 1530 connecting themedia/buffer plant 1520 to each respective customizable facility 1510 tosupply each customizable facility 1510 with media for manufacturing thepharmaceutical product(s).

In some embodiments, the supply line 1530 is a connecting corridor thatconnects the media/buffer plant 1520 to each customizable facility 1510.In some embodiments, the connecting corridor is a covered walkway thatis 6 meters high. Employees or automated vehicles can transport aprocessing material such as buffer or media through the connectingcorridor to deliver the processing material to each customizablefacility 1510.

In some aspects, a utility building 1540 is connected by a utility line1550 to the media/buffer plant 1520 to provide at least one firstutility to the media/buffer plant 1520 via the utility line 1550. Forexample, the utility building 1540 can provide an air supply and a steamsupply to the media/buffer plant 1520 in FIG. 12. The utility building1540 can be configured to deliver or otherwise provide utilities to themedia/buffer plant 1520 and/or the customizable facilities 1510. Theutility building 1540 is positioned adjacent one of the customizablefacilities 1510. In some aspects, the utility building 1540 is optional.

In some embodiments, the utility building 1540 also includes one or moreutility lines connected to each customizable facility 1510, so that theutility building 1540 supplies utilities to the media/buffer plant 1520and to the each customizable facility 1510. In some embodiments, theutility building 1540 can be used to provide utilities to any of themedia/buffer plant 1520, the customizable facilities 1510, a warehouse1560, and any other buildings on the campus.

The media/buffer plant area is distinct from the downstream processingarea(s) in the manufacturing wing(s) of each customizable facility 1510.While the media/buffer plant and the customizable facilities 1510 are onthe same campus 1500, no proximity is required as long as theconcentrated solutions can be delivered from the media/buffer plant 1520to the downstream processing area(s) within each customizable facility1510 without adversely affecting the stability or activity of thesolutions. Scheduling, formulation, and delivery of the solutions areperformed to prepare the solutions at or just before their intended timeof use. This arrangement reduces storage space at the site of thebioreactor, and allows multiple manufacturers to share expensesassociated with the media/buffer plant 1520.

In some embodiments, a first floor of a respective one of thecustomizable facilities 1510 includes a utilities area.

The warehouse 1560 is positioned adjacent one of the customizablefacilities 1510 in FIG. 12. A user may store materials in the warehouse1560 and then transport the materials from the warehouse 1560 to anotherbuilding on the campus 1500, such as one of the customizable facilities1510 on the campus. In some aspects, the warehouse is optional.

Each customizable facility 1510 can be configured to manufacturedifferent pharmaceutical products from the other customizable facilities1510 on the campus 1500. Moreover, as described herein, eachcustomizable facility 1510 can be configured to produce a plurality ofdrug products utilizing modules, wings or suites within the customizablefacility.

FIG. 13 shows an enlarged view of a portion of the campus 1500, showingone of the customizable facilities 1510 of FIG. 12 in further detail.The customizable facility 1510 of FIG. 13 includes different modules. Inparticular, the customizable facility 1510 of FIG. 13 includes an officemodule 1570, a gown module 1580, a utilities module 1590, and twomanufacturing wings 1600A, 1600B.

The manufacturing wing 1600A can be configured so that it has threemanufacturing modules 1610, which each may be used by a differentmanufacturer to manufacture a different pharmaceutical product. Eachmanufacturing module 1610 has its own dedicated access within thecustomizable facility 1510, with independent routes from the gown module1580 to the respective manufacturing module 1610. The manufacturing wing1600B can be configured to have a plurality of manufacturing modules ina manner similar to the manufacturing wing 1600A.

In some embodiments of the campus 1500, the first manufacturing wing1600A of at least one of the customizable facilities 1510 is pre-builtand available for use to manufacture at least one pharmaceuticalproduct. When the first manufacturing wing 1600A is being entirelyutilized for manufacturing operations, the user can build out the secondmanufacturing wing 1600B to be technology agnostic from the firstmanufacturing wing 1600A, meaning the second manufacturing wing 1600B isgenerally configured for a wide range of manufacturing operations toproduce a wide range of manufactured products that can be different thanthe pharmaceutical product produced by the first manufacturing wing1600A. Because the manufacturing wings 1600A, 1600B are technologyagnostic, the campus 1500 provides flexible manufacturing options to auser. In some embodiments, the second manufacturing wing 1600B can beconfigured to be built within the respective customizable facility 1510before the user requires additional manufacturing space. In this manner,additional manufacturing wings are built up in the five customizablefacilities 1510 on the campus 1500. For example, when five manufacturingwings are being used for manufacturing pharmaceutical products, the userbuilds out a sixth manufacturing wing. By building out an additionalmanufacturing wing in excess of what is needed for manufacturing space,the user ensures that the customizable facility does not have 100%utilization of the manufacturing wings until all ten manufacturing wings(two manufacturing wings in each of the five customizable facilities1510 of FIG. 12) are being used for manufacturing pharmaceuticalproducts.

The utilities module 1590 can also be identified as a central unit, andprovides at least one second utility to the modular units of thecustomizable facility 1510, which are the office module 1570, the gownmodule 1580, the utilities module 1590, and the two manufacturing wings1600A, 1600B in the embodiment of FIG. 12.

In some embodiments of the campus 1500, the utility building 1540 isconnected to each of the customizable facilities 1510, and the firstutility is the same as the second utility. In such embodiments, theutilities module 1590 supplements the utilities provided to the modularunits of the respective customizable facility 1510 by the utilitybuilding 1540. In some embodiments, the first utility is different fromthe second utility.

In some embodiments of the campus 1500, each customizable facility 1510may be a customizable facility as described above in relation to FIGS.1-11. For example, in some embodiments, the customizable facility 1510includes at least one central unit, and at least one modular unit incommunication with the at least one central unit such that the at leastone central unit provides at least one second utility to the at leastone modular unit.

In some embodiments, the one or more modular units includes afermentation unit, a pre-viral unit, a post-viral unit, a utility space,a warehouse, a media/buffer plant, an office, a personnel unit, aproduction unit, a fill-finish unit, a dosage formulation unit, and/or apackaging unit.

Although a shell is not shown in FIGS. 12 and 13, each customizablefacility 1510 includes a shell, similar to the shell in the embodimentsof the customizable facility described in relation to FIGS. 1-2E or FIG.4, or another embodiment of the customizable facility of the presentdisclosure.

In some embodiments, the one or more central unit(s) are positioned atleast partially within the shell, and the one or more modular unit(s)are positioned at least partially within the shell.

In some embodiments, the customizable facility includes a plurality ofmodular units arranged to maximize a number of modular units within theshell while minimizing a footprint of the shell.

In some embodiments of the campus 1500, an outer wall of at least one ofthe customizable facilities 1510 is formed by the shell of thatcustomizable facility 1510, and the respective shell entirely enclosesthe one or more central units and the at least one modular units of thatcustomizable facility 1510. In some embodiments of the campus 1500, theouter wall of at least one of the customizable facilities 1510 is formedby the shell of that customizable facility 1510 and at least one of anouter wall of the one or more central units of that customizablefacility 1510 and an outer wall of the one or more modular units of thatcustomizable facility 1510. In some embodiments, the shell includes atleast one side wall, the at least one side wall encircling the one ormore central units and the one or more modular units. A roof is securedto an upper edge of the at least one side wall, the roof extending overthe one or more central units and the one or more modular units.

The build-out of manufacturing wings in the customizable facilities onthe campus is fast and cost-effective. The campus provides fasterproduction line development timelines. Because at least onemanufacturing wing is pre-built and available for use, a manufacturercan reduce time-to-market by 12 months in some embodiments, and by 16months in some embodiments. In some embodiments, the campus allows auser to decrease time-to-market from four-and-a-half years to two years.In some embodiments, the campus allows a user to decreasetime-to-market, for example from three years to two years.Pharmaceutical manufacturers can easily scale-up or scale-down theirmanufacturing line as needed.

The campus reduces financial and operational risks to the manufacturer.The campus allows a manufacturer to more easily deal with uncertainty indemand for a pharmaceutical over time. The campus of the presentdisclosure allows manufacturers to respond rapidly as their needsevolve.

The campus provides the utilities and support technologies in one place,by providing buildings such as the utilities building 1540, warehouse1560, and media/buffer plant 1520 that can be commonly used by each ofthe customizable facilities 1510. The campus includes dedicatedfacilities with state-of-the-art technology. For example, eachmanufacturer can benefit from the state-of-the-art media/buffer plant,utilities building, and other facilities on the campus.

In some embodiments, more or fewer than five customizable facilities1510 may be included on the campus 1500. In some aspects, the campus canbe iteratively constructed over time such that a first customizablefacility is constructed and then, once capacity is reached in the firstfacility, a second customizable facility is brought online, and so on.

According to an aspect of the present disclosure, a method of assemblinga campus for manufacturing at least one pharmaceutical product isprovided. A customizable facility that is configured to manufacture theat least one pharmaceutical product is provided. The customizablefacility is configured as an embodiment of a customizable facilitydescribed above in relation to FIGS. 1-13. A media/buffer plant isprovided, and is useful for producing media/buffer that can be deliveredto manufacturing module on the campus. In some aspects, the media/bufferplant is operatively coupled and/or configured to provide or supply theat least one customizable facility with a processing material, such asbut not limited to media or buffer. In some aspects, the media/bufferplant may be configured to provide the processing material in atransportable container, such as a bag, and transport the processingmaterial to the customizable facility via truck, rail, or other groundtransport system on the campus. In some aspects, the campus can includea supply line, with the respective supply line connecting themedia/buffer plant to each respective customizable facility to supplyeach customizable facility with media for manufacturing thepharmaceutical product(s).

A first end of a utility line is connected to a utility building and asecond end of the utility line is connected to the media/buffer plant toprovide at least one first utility to the media/buffer plant via theutility line. For example, the first utility can be steam and/or an airsupply. A warehouse is positioned adjacent the customizable facility,and is useful for providing materials to the customizable facility. Themedia/buffer plant is positioned adjacent the customizable facility, andthe utility building is positioned adjacent the customizable facility.

When the first manufacturing wing 1600A in one of the customizablefacilities is being entirely utilized for manufacturing operations, themethod includes building out the second manufacturing wing 1600B in therespective customizable facility.

FIG. 14 shows a perspective view of the five customizable facilities1510, the media/buffer plant 1520, the utility building 1540 constructedaccording to the schematic of FIG. 12.

FIG. 15 shows a customizable facility 1710 having a first manufacturingwing 1800A and a second manufacturing wing 1800B. The firstmanufacturing wing 1800A includes a first manufacturing module 1810A anda second manufacturing module 1810B. The second manufacturing wing 1800Bincludes a third manufacturing module 1810C. Each manufacturing module1810A, 1810B, 1810C is a modular unit within its respectivemanufacturing wing 1800A, 1800B. Each manufacturing module 1810A, 1810B,1810C can be operated, owned, or leased by a different manufacturer. Inembodiments in which one of the manufacturing modules 1810A, 1810B,1810C is leased, the module can be leased from an owner of therespective manufacturing module 1810A, 1810B, 1810C. In someembodiments, the owner of a manufacturing module may be an owner of thecampus or an owner of the customizable facility 1710.

Each manufacturer can use a different gown area. In a certainembodiment, a first manufacturer has its own dedicated access to thefirst manufacturing module 1810A and dedicated access to a first gownarea 1820A. Only workers associated with the first manufacturer canenter the first gown area 1820A. Only workers associated with the firstmanufacturer can enter the first manufacturing module 1810A, which isaccessible via a first dedicated access route 1880A from the first gownarea 1820A to the first manufacturing module 1810A.

With this embodiment, a second manufacturer has its own dedicated accessto the second manufacturing module 1810B and dedicated access to asecond gown area 1820B. Only workers associated with the secondmanufacturer can enter the second gown area 1820B. Only workersassociated with the second manufacturer can enter the secondmanufacturing module 1810B, which is accessible via a second dedicatedaccess route 1880B from the second gown area 1820B to the secondmanufacturing module 1810B.

Continuing with this embodiment, a third manufacturer has its owndedicated access to the third manufacturing module 1810C and dedicatedaccess to a third gown area 1820C. Only workers associated with thethird manufacturer can enter the third gown area 1820C. Only workersassociated with the third manufacturer can enter the third manufacturingmodule 1810C, which is accessible via a third dedicated access route1880C from the third gown area 1820C to the third manufacturing module1810C.

The customizable facility 1710 includes a utility module 1890 thatprovides utilities to the other modules in the customizable facility1710, such as the first manufacturing module 1810A, the secondmanufacturing module 1810B, and the third manufacturing module 1810C.

The customizable facility of FIG. 15 can be included on a campus of thepresent disclosure, such as the campus 1500 of FIG. 12.

Because the customizable facility 1710 includes manufacturing modules1810A, 1810B, 1810C that each has a respective dedicated access route1880A, 1880B, 1880C, the manufacturing modules 1810A, 1810B, 1810C arecordoned off from one another. This prevents cross-contamination ofemployees of the respective manufacturers. The cordoning off of thethree manufacturing modules 1810A, 1810B, 1810C also preventscross-contamination of products manufactured by the respectivemanufacturers. For example, this prevents the spread of pathogens fromone of the manufacturing modules within the customizable facility 1710to another one of the manufacturing modules within the customizablefacility 1710.

The utility module 1890 provides shared utilities to the threemanufacturing modules 1810A, 1810B, 1810C. Similarly, when thecustomizable facility 1710 is incorporated into a campus, such as acampus shown in FIG. 12 or FIG. 14, a utility building 1540 is capableof being connected to the three manufacturing modules 1810A, 1810B,1810C to deliver utilities to the three manufacturing modules 1810A,1810B, 1810C.

In this way, the customizable facility 1710 provides shared utilities,while providing a secure, isolated manufacturing environment for amanufacturer within a manufacturing module.

According to an aspect of the present disclosure, a method of managing apharmaceutical facility is provided. The method includes providing acampus for fabricating one or more pharmaceutical products. In someembodiments, the campus can be a campus described herein, such as thecampus 1500 of FIG. 12. For example, in some embodiments, the campusincludes at least one customizable facility configured to manufactureone or more pharmaceutical products. In some embodiments, the campusfurther includes a media/buffer plant. In some embodiments, the campusfurther includes a bagging unit in the media/buffer plant at whichmedia/buffer is bagged so it can be moved by ground transportation tothe customizable facility. In some aspects, the media/buffer plant isoperatively coupled and/or configured to provide or supply the at leastone customizable facility with a processing material, such as but notlimited to media or buffer. In some aspects, the media/buffer plant maybe configured to provide the processing material in a transportablecontainer, such as a bag, and transport the processing material to thecustomizable facility via truck, rail, or other ground transport systemon the campus. In some aspects, the campus can include a supply line,with the respective supply line connecting the media/buffer plant toeach respective customizable facility to supply each customizablefacility with media for manufacturing the pharmaceutical product(s)

In some embodiments, the campus further includes a utility buildingconnected by a utility line to the media/buffer plant to provide atleast one first utility to the media/buffer plant via the utility line.The method of managing the pharmaceutical facility further includesoffering at least a portion of the campus (for example, through a sale,a lease or another contract) to a customer desiring to manufacture apharmaceutical product.

In some embodiments, the portion of the campus that is offered to acustomer includes a manufacturing wing in one of the customizablefacilities on the campus.

In some embodiments, the portion of the campus that is offered to acustomer includes a manufacturing module within one of the manufacturingwings in one of the customizable facilities on the campus.

This method of managing the pharmaceutical facility can be carried outby an owner of the campus. In some embodiments, the owner of the campusoffers a customer a first option to buy a portion of the campus and asecond option to lease a portion of the campus from the owner. In someembodiments, the owner of the campus only offers a customer an option tobuy a portion of the campus. For example, the owner of the campus couldoffer a customer an option to buy a portion of a customizable facilitythat is on the campus. In particular, the owner of the campus couldoffer a customer an option to buy a manufacturing module within thecustomizable facility. In some embodiments, the owner of the campus onlyoffers a customer an option to lease a portion of the campus. Forexample, the owner of the campus could offer a customer an option tolease a portion of a customizable facility. In particular, the owner ofthe campus could offer a customer an option to lease a manufacturingmodule within the customizable facility.

In some embodiments, the owner of the campus could offer a customeranother option, such as an option in which the customer rents a portionof the campus for a first period of time and then the customer canchoose whether to buy the portion of the campus at the end of the firstperiod of time. Additional ownership and rental options are also withinthe scope of the present disclosure. In some embodiments, the owner ofthe campus offers to assign its own employees to manufacture apharmaceutical product within the offered portion of the campus onbehalf of a customer.

According to an aspect of the present disclosure, a method of adjustinga capacity of a pharmaceutical facility is provided. The method ofadjusting the capacity includes providing a campus for fabricating atleast one pharmaceutical product. In some embodiments, the campus can bea campus described herein, such as the campus 1500 of FIG. 12. Forexample, in some embodiments, the campus includes at least onecustomizable facility configured to manufacture one or morepharmaceutical products. In some embodiments, the campus furtherincludes a media/buffer plant. In some embodiments, the campus furtherincludes a bagging unit in the media/buffer plant at which media/bufferis bagged so it can be moved by ground transportation to thecustomizable facility. In some aspects, the media/buffer plant isoperatively coupled and/or configured to provide or supply the at leastone customizable facility with a processing material, such as but notlimited to media or buffer. In some aspects, the media/buffer plant maybe configured to provide the processing material in a transportablecontainer, such as a bag, and transport the processing material to thecustomizable facility via truck, rail, or other ground transport systemon the campus. In some aspects, the campus can include a supply line,with the respective supply line connecting the media/buffer plant toeach respective customizable facility to supply each customizablefacility with media for manufacturing the pharmaceutical product(s)

In some embodiments, the campus further includes a utility buildingconnected by a utility line to the media/buffer plant to provide atleast one first utility to the media/buffer plant via the utility line.The method of managing the pharmaceutical facility further includesoffering at least a portion of the campus to a customer desiring tomanufacture a pharmaceutical product.

The method further includes offering at least a first portion of thecampus to a first customer desiring to manufacture a firstpharmaceutical product. The method further includes constructing atleast a second portion of the campus for manufacturing a secondpharmaceutical product. The second portion is technology agnostic. Forexample, the owner of the campus can offer a first manufacturing moduleto a first customer that desires to manufacture a first pharmaceuticalproduct. The owner of the campus constructs a second manufacturingmodule (or otherwise ensures that a second manufacturing module isavailable for use by a second customer). This second manufacturingmodule is technology agnostic.

In some embodiments, the second manufacturing module can be subsequentlyused by a manufacturer to manufacture a second product, which can bedifferent from the first product or identical to the first product.

In some embodiments, the owner of the campus then offers the at leastthe second portion of the campus to a second customer. The owner of thecampus constructs a third manufacturing module (or otherwise ensuresthat a third manufacturing module is available for use by a thirdcustomer). This third manufacturing module is technology agnostic.

By building out an additional portion of the campus in excess of what isneeded for manufacturing space, the user ensures that the customizablefacility does not have 100% utilization of the manufacturing wings untilall of the manufacturing wings on the campus are being used formanufacturing pharmaceutical products.

In some embodiments, the owner of the campus offers a first customer afirst portion of the campus that is accessible only via a firstdedicated access route that is accessible by the first customer, butthat is not accessible by the second customer. The owner of the campusoffers a second customer a second portion of the campus that isaccessible only via a second dedicated access route that is accessibleby the second customer, but that is not accessible by the firstcustomer. The first portion and the second portion do not need to belimited to manufacturing modules.

In some embodiments, the owner of the campus continually maintains atechnology agnostic portion of the campus in a ready state for a newcustomer to begin manufacturing a pharmaceutical. This allows the ownerof the campus to quickly respond to changes in demand for apharmaceutical. The technology agnostic portion of the campus that is inthe ready state for the new customer to begin manufacturing apharmaceutical can be quickly rented, leased, sold, or otherwise used bya new customer or an existing customer to meet market demand for apharmaceutical.

The methods of managing a pharmaceutical facility and of adjusting acapacity of a pharmaceutical facility can be performed by an owner of acampus or another party, such as an operator of a campus or a partyacting on behalf of the owner of the campus.

Example of a Fermentation Unit

The fermentation unit 116B houses equipment suitable for cell cultureand/or fermentation. For example, equipment for cell culture andfermentation include, but are not limited to, bioreactors (e.g.,suitable for culturing cells or fermentation), tanks (e.g., suitable forhousing cells, media or products produced by cells), decantingapparatus, centrifuges, pumps, and other equipment useful for productrecovery. Refold tanks and microfiltration units would be included formicrobial fermentation processes.

In one embodiment, the fermentation unit 116B contains one or morebioreactor units suitable for culturing cells. A bioreactor unit canperform one or more, or all, of the following: feeding of nutrientsand/or carbon sources, injection of suitable gas (e.g., oxygen), flow offermentation or cell culture medium, separation of gas and liquidphases, maintenance of growth temperature, maintenance of pH level,agitation (e.g., stirring), and/or cleaning/sterilizing. Thefermentation unit may contain one, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35,40, 45, 50, 60, 70, 80, 90, or 100, or more bioreactors. In variousembodiments, the bioreactor is suitable for batch, semi fed-batch,fed-batch, perfusion, and/or continuous fermentation processes. In oneembodiment, the bioreactor is a stirred tank reactor. In one embodiment,the bioreactor is an airlift reactor. In one embodiment, the bioreactorcan have a volume between about 100 milliliters and about 50,000 liters.Non-limiting examples include a volume of 100 milliliters, 250milliliters, 500 milliliters, 750 milliliters, 1 liter, 2 liters, 3liters, 4 liters, 5 liters, 6 liters, 7 liters, 8 liters, 9 liters, 10liters, 15 liters, 20 liters, 25 liters, 30 liters, 40 liters, 50liters, 60 liters, 70 liters, 80 liters, 90 liters, 100 liters, 150liters, 200 liters, 250 liters, 300 liters, 350 liters, 400 liters, 450liters, 500 liters, 550 liters, 600 liters, 650 liters, 700 liters, 750liters, 800 liters, 850 liters, 900 liters, 950 liters, 1000 liters,1500 liters, 2000 liters, 2500 liters, 3000 liters, 3500 liters, 4000liters, 4500 liters, 5000 liters, 6000 liters, 7000 liters, 8000 liters,9000 liters, 10,000 liters, 15,000 liters, 20,000 liters, or 50,000liters.

In one embodiment, the bioreactor is suitable for culturing suspensioncells or anchorage-dependent (adherent) cells. In one embodiment, thefermentation suite is suitable for cell therapy and/or viral therapyoperations. In one embodiment, the bioreactor is suitable for culturingprokaryotic cells or eukaryotic cells. Examples of cells include, butare not limited to, bacterial cells (e.g., E. coli. P. pastoris), yeastcells (e.g., S. cerevisae, T. reesei), plant cells, insect cells (e.g.,Sf9), Chinese hamster ovary cells (CHO, and any genetically modified orderived CHO cell line), mouse cells (e.g., mouse embryonic fibroblasts,cells derived from mouse cancer models), human cells (e.g., cells fromany tissue or organ, cells from a cancer or other diseased cell line,stem cell), hybridoma cells, or other genetically modified or hybridcells. In one embodiment, the cells express or produce a product, suchas a recombinant therapeutic or diagnostic product. Examples of productsproduced by cells include, but are not limited to, antibody molecules(e.g., monoclonal antibodies, bispecific antibodies), fusion proteins(e.g., Fc fusion proteins, chimeric cytokines), other recombinantproteins (e.g., glycosylated proteins, enzymes, hormones), orlipid-encapsulated particles (e.g., exosomes, virus-like particles). Inembodiments, the fermentation unit also contains equipment forseparation, purification, and isolation of such products from the cells.In one embodiment, the facility and/or bioreactor can be used forproducing biosimilar products.

In embodiments, the fermentation unit is in compliance with goodmanufacturing process and biological safety standards. In oneembodiment, the fermentation unit is compliant with biosafety level 1(BSL1), biosafety level 2 (BSL2), biosafety level 3 (BSL3), or biosafetylevel 4 (BSL4).

The fermentation unit can comprise sub-compartments in which eachsub-compartment can be used to perform a different function or aspectthat supports the cell culture, fermentation, and production processes.By way of example, the fermentation unit comprises a sub-compartmentthat houses one or more bioreactors, a sub-compartment that housesequipment for product recovery, a sub-compartment for inoculum, and asub-compartment for cleaning and decontamination of equipment and theoperators handling such equipment.

Example of a Down Stream Processing Unit

The purification units 116A discussed above are examples of downstreamprocessing units.

As one example, a standard downstream processing (DSP) unit includespre-viral separation and post-viral separation sub-units. While viralreduction does occur throughout a typical mammalian cell derived proteinpurification, the critical viral reduction step is considered to be theappropriate point for spatial segregation with the post-viral separationsub-unit to be considered essentially virus free. The post-viralseparation sub-unit houses equipment and utilities suitable for any oneof the following: ultrafiltration (tangential filtration), normalfiltration, chromatography, formulation, titration, mixing,concentration, buffer exchange, bulk drug substance container fillingand freezing.

The descriptions of the various embodiments and/or examples of thepresent disclosure have been presented for purposes of illustration, butare not intended to be exhaustive or limited to the embodimentsdisclosed. Many modifications and variations will be apparent to thoseof ordinary skill in the art without departing from the scope and spiritof the described embodiments. The terminology used herein was chosen tobest explain the principles of the embodiments, the practicalapplication or technical improvement over technologies found in themarketplace, or to enable others of ordinary skill in the art tounderstand the embodiments disclosed herein.

The descriptions of the various embodiments of the present disclosurecan be utilized in the production of pharmaceuticals andbiopharmaceutical products. The devices, facilities and methodsdescribed herein are suitable for culturing any desired cell lineincluding prokaryotic and/or eukaryotic cell lines. Further, inembodiments, the devices, facilities and methods are suitable forculturing suspension cells or anchorage-dependent (adherent) cells andare suitable for production operations configured for production ofpharmaceutical and biopharmaceutical products—such as polypeptideproducts, nucleic acid products (for example DNA or RNA), or cellsand/or viruses such as those used in cellular and/or viral therapies.

In embodiments, the cells express or produce a product, such as arecombinant therapeutic or diagnostic product. As described in moredetail below, examples of products produced by cells include, but arenot limited to, antibody molecules (e.g., monoclonal antibodies,bispecific antibodies), antibody mimetics (polypeptide molecules thatbind specifically to antigens but that are not structurally related toantibodies such as e.g. DARPins, affibodies, adnectins, or IgNARs),fusion proteins (e.g., Fc fusion proteins, chimeric cytokines), otherrecombinant proteins (e.g., glycosylated proteins, enzymes, hormones),viral therapeutics (e.g., anti-cancer oncolytic viruses, viral vectorsfor gene therapy and viral immunotherapy), cell therapeutics (e.g.,pluripotent stem cells, mesenchymal stem cells and adult stem cells),vaccines or lipid-encapsulated particles (e.g., exosomes, virus-likeparticles), RNA (such as e.g. siRNA) or DNA (such as e.g. plasmid DNA),antibiotics or amino acids. In embodiments, the devices, facilities andmethods can be used for producing biosimilars.

As mentioned, in embodiments, devices, facilities and methods allow forthe production of eukaryotic cells, e.g., mammalian cells or lowereukaryotic cells such as for example yeast cells or filamentous fungicells, or prokaryotic cells such as Gram-positive or Gram-negative cellsand/or products of the eukaryotic or prokaryotic cells, e.g., proteins,peptides, antibiotics, amino acids, nucleic acids (such as DNA or RNA),synthesised by the eukaryotic cells in a large-scale manner. Unlessstated otherwise herein, the devices, facilities, and methods caninclude any desired volume or production capacity including but notlimited to bench-scale, pilot-scale, and full production scalecapacities.

Moreover and unless stated otherwise herein, the devices, facilities,and methods can include any suitable reactor(s) including but notlimited to stirred tank, airlift, fiber, microfiber, hollow fiber,ceramic matrix, fluidized bed, fixed bed, and/or spouted bedbioreactors. As used herein, “reactor” can include a fermentor orfermentation unit, or any other reaction vessel and the term “reactor”is used interchangeably with “fermentor.” For example, in some aspects,an example bioreactor unit can perform one or more, or all, of thefollowing: feeding of nutrients and/or carbon sources, injection ofsuitable gas (e.g., oxygen), inlet and outlet flow of fermentation orcell culture medium, separation of gas and liquid phases, maintenance oftemperature, maintenance of oxygen and CO2 levels, maintenance of pHlevel, agitation (e.g., stirring), and/or cleaning/sterilizing. Examplereactor units, such as a fermentation unit, may contain multiplereactors within the unit, for example the unit can have 1, 2, 3, 4, 5,10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100, or morebioreactors in each unit and/or a facility may contain multiple unitshaving a single or multiple reactors within the facility. In variousembodiments, the bioreactor can be suitable for batch, semi fed-batch,fed-batch, perfusion, and/or a continuous fermentation processes. Anysuitable reactor diameter can be used. In embodiments, the bioreactorcan have a volume between about 100 mL and about 50,000 L. Non-limitingexamples include a volume of 100 milliliters, 250 milliliters, 500milliliters, 750 milliliters, 1 liter, 2 liters, 3 liters, 4 liters, 5liters, 6 liters, 7 liters, 8 liters, 9 liters, 10 liters, 15 liters, 20liters, 25 liters, 30 liters, 40 liters, 50 liters, 60 liters, 70liters, 80 liters, 90 liters, 100 liters, 150 liters, 200 liters, 250liters, 300 liters, 350 liters, 400 liters, 450 liters, 500 liters, 550liters, 600 liters, 650 liters, 700 liters, 750 liters, 800 liters, 850liters, 900 liters, 950 liters, 1000 liters, 1500 liters, 2000 liters,2500 liters, 3000 liters, 3500 liters, 4000 liters, 4500 liters, 5000liters, 6000 liters, 7000 liters, 8000 liters, 9000 liters, 10,000liters, 15,000 liters, 20,000 liters, and/or 50,000 liters.Additionally, suitable reactors can be multi-use, single-use,disposable, or non-disposable and can be formed of any suitable materialincluding metal alloys such as stainless steel (e.g., 316L or any othersuitable stainless steel) and Inconel, plastics, and/or glass.

In embodiments and unless stated otherwise herein, the devices,facilities, and methods described herein can also include any suitableunit operation and/or equipment not otherwise mentioned, such asoperations and/or equipment for separation, purification, and isolationof such products. Any suitable facility and environment can be used,such as traditional stick-built facilities, modular, mobile andtemporary facilities, or any other suitable construction, facility,and/or layout. For example, in some embodiments modular clean-rooms canbe used. Additionally and unless otherwise stated, the devices, systems,and methods described herein can be housed and/or performed in a singlelocation or facility or alternatively be housed and/or performed atseparate or multiple locations and/or facilities.

By way of non-limiting examples and without limitation, U.S. PublicationNos. 2013/0280797; 2012/0077429; 2009/0305626; and U.S. Pat. Nos.8,298,054; 7,629,167; and 5,656,491, which are hereby incorporated byreference in their entirety, describe example facilities, equipment,and/or systems that may be suitable.

In embodiments, the cells are eukaryotic cells, e.g., mammalian cells.The mammalian cells can be for example human or rodent or bovine celllines or cell strains. Examples of such cells, cell lines or cellstrains are e.g. mouse myeloma (NSO)-cell lines, Chinese hamster ovary(CHO)-cell lines, HT1080, H9, HepG2, MCF7, MDBK Jurkat, NIH3T3, PC12,BHK (baby hamster kidney cell), VERO, SP2/0, YB2/0, YO, C127, L cell,COS, e.g., COS1 and COST, QC1-3,HEK-293, VERO, PER.C6, HeLA, EB1, EB2,EB3, oncolytic or hybridoma-cell lines. Preferably the mammalian cellsare CHO-cell lines. In one embodiment, the cell is a CHO cell. In oneembodiment, the cell is a CHO-K1 cell, a CHO-K1 SV cell, a DG44 CHOcell, a DUXB11 CHO cell, a CHOS, a CHO GS knock-out cell, a CHO FUT8 GSknock-out cell, a CHOZN, or a CHO-derived cell. The CHO GS knock-outcell (e.g., GSKO cell) is, for example, a CHO-K1 SV GS knockout cell.The CHO FUT8 knockout cell is, for example, the Potelligent® CHOK1 SV(Lonza Biologics, Inc.). Eukaryotic cells can also be avian cells, celllines or cell strains, such as for example, EBx® cells, EB14, EB24,EB26, EB66, or EBv13.

In one embodiment, the eukaryotic cells are stem cells. The stem cellscan be, for example, pluripotent stem cells, including embryonic stemcells (ESCs), adult stem cells, induced pluripotent stem cells (iPSCs),tissue specific stem cells (e.g., hematopoietic stem cells) andmesenchymal stem cells (MSCs).

In one embodiment, the cell is a differentiated form of any of the cellsdescribed herein. In one embodiment, the cell is a cell derived from anyprimary cell in culture.

In embodiments, the cell is a hepatocyte such as a human hepatocyte,animal hepatocyte, or a non-parenchymal cell. For example, the cell canbe a plateable metabolism qualified human hepatocyte, a plateableinduction qualified human hepatocyte, plateable Qualyst TransporterCertified™ human hepatocyte, suspension qualified human hepatocyte(including 10-donor and 20-donor pooled hepatocytes), human hepatickupffer cells, human hepatic stellate cells, dog hepatocytes (includingsingle and pooled Beagle hepatocytes), mouse hepatocytes (including CD-1and C57BI/6 hepatocytes), rat hepatocytes (including Sprague-Dawley,Wistar Han, and Wistar hepatocytes), monkey hepatocytes (includingCynomolgus or Rhesus monkey hepatocytes), cat hepatocytes (includingDomestic Shorthair hepatocytes), and rabbit hepatocytes (including NewZealand White hepatocytes). Example hepatocytes are commerciallyavailable from Triangle Research Labs, LLC, 6 Davis Drive ResearchTriangle Park, N.C., USA 27709.

In one embodiment, the eukaryotic cell is a lower eukaryotic cell suchas e.g. a yeast cell (e.g., Pichia genus (e.g. Pichia pastoris, Pichiamethanolica, Pichia kluyveri, and Pichia angusta), Komagataella genus(e.g. Komagataella pastoris, Komagataella pseudopastoris or Komagataellaphaffii), Saccharomyces genus (e.g. Saccharomyces cerevisae, cerevisiae,Saccharomyces kluyveri, Saccharomyces uvarum), Kluyveromyces genus (e.g.Kluyveromyces lactis, Kluyveromyces marxianus), the Candida genus (e.g.Candida utilis, Candida cacaoi, Candida boidinii,), the Geotrichum genus(e.g. Geotrichum fermentans), Hansenula polymorpha, Yarrowia lipolytica,or Schizosaccharomyces pombe. Preferred is the species Pichia pastoris.Examples for Pichia pastoris strains are X33, GS115, KM71, KM71H; andCBS7435.

In one embodiment, the eukaryotic cell is a fungal cell (e.g.Aspergillus (such as A. niger, A. fumigatus, A. orzyae, A. nidula),Acremonium (such as A. thermophilum), Chaetomium (such as C.thermophilum), Chrysosporium (such as C. thermophile), Cordyceps (suchas C. militaris), Corynascus, Ctenomyces, Fusarium (such as F.oxysporum), Glomerella (such as G. graminicola), Hypocrea (such as H.jecorina), Magnaporthe (such as M. orzyae), Myceliophthora (such as M.thermophile), Nectria (such as N. heamatococca), Neurospora (such as N.crassa), Penicillium, Sporotrichum (such as S. thermophile), Thielavia(such as T. terrestris, T. heterothallica), Trichoderma (such as T.reesei), or Verticillium (such as V. dahlia)).

In one embodiment, the eukaryotic cell is an insect cell (e.g., Sf9,Mimic™ Sf9, Sf21, High Five™ (BT1-TN-5B1-4), or BT1-Ea88 cells), analgae cell (e.g., of the genus Amphora, Bacillariophyceae, Dunaliella,Chlorella, Chlamydomonas, Cyanophyta (cyanobacteria), Nannochloropsis,Spirulina, or Ochromonas), or a plant cell (e.g., cells frommonocotyledonous plants (e.g., maize, rice, wheat, or Setaria), or froma dicotyledonous plants (e.g., cassava, potato, soybean, tomato,tobacco, alfalfa, Physcomitrella patens or Arabidopsis).

In one embodiment, the cell is a bacterial or prokaryotic cell.

In embodiments, the prokaryotic cell is a Gram-positive cells such asBacillus, Streptomyces Streptococcus, Staphylococcus or Lactobacillus.Bacillus that can be used is, e.g. the B. subtilis, B.amyloliquefaciens, B. licheniformis, B. natto, or B. megaterium. Inembodiments, the cell is B. subtilis, such as B. subtilis 3NA and B.subtilis 168. Bacillus is obtainable from, e.g., the Bacillus GeneticStock Center, Biological Sciences 556, 484 West 12^(th) Avenue, ColumbusOhio 43210-1214.

In one embodiment, the prokaryotic cell is a Gram-negative cell, such asSalmonella spp. or Escherichia coli, such as e.g., TG1, TG2, W3110, DH1,DHB4, DH5a, HMS 174, HMS174 (DE3), NM533, C600, HB101, JM109, MC4100,XL1-Blue and Origami, as well as those derived from E. coli B-strains,such as for example BL-21 or BL21 (DE3), all of which are commerciallyavailable.

Suitable host cells are commercially available, for example, fromculture collections such as the DSMZ (Deutsche Sammlung vonMikroorganismen and Zellkulturen GmbH, Braunschweig, Germany) or theAmerican Type Culture Collection (ATCC).

In embodiments, the cultured cells are used to produce proteins e.g.,antibodies, e.g., monoclonal antibodies, and/or recombinant proteins,for therapeutic use. In embodiments, the cultured cells producepeptides, amino acids, fatty acids or other useful biochemicalintermediates or metabolites. For example, in embodiments, moleculeshaving a molecular weight of about 4000 daltons to greater than about140,000 daltons can be produced. In embodiments, these molecules canhave a range of complexity and can include posttranslationalmodifications including glycosylation.

In embodiments, the protein is, e.g., BOTOX, Myobloc, Neurobloc, Dysport(or other serotypes of botulinum neurotoxins), alglucosidase alpha,daptomycin, YH-16, choriogonadotropin alpha, filgrastim, cetrorelix,interleukin-2, aldesleukin, teceleulin, denileukin diftitox, interferonalpha-n3 (injection), interferon alpha-nl, DL-8234, interferon, Suntory(gamma-1a), interferon gamma, thymosin alpha 1, tasonermin, DigiFab,ViperaTAb, EchiTAb, CroFab, nesiritide, abatacept, alefacept, Rebif,eptoterminalfa, teriparatide (osteoporosis), calcitonin injectable (bonedisease), calcitonin (nasal, osteoporosis), etanercept, hemoglobinglutamer 250 (bovine), drotrecogin alpha, collagenase, carperitide,recombinant human epidermal growth factor (topical gel, wound healing),DWP401, darbepoetin alpha, epoetin omega, epoetin beta, epoetin alpha,desirudin, lepirudin, bivalirudin, nonacog alpha, Mononine, eptacogalpha (activated), recombinant Factor VIII+VWF, Recombinate, recombinantFactor VIII, Factor VIII (recombinant), Alphnmate, octocog alpha, FactorVIII, palifermin,Indikinase, tenecteplase, alteplase, pamiteplase,reteplase, nateplase, monteplase, follitropin alpha, rFSH, hpFSH,micafungin, pegfilgrastim, lenograstim, nartograstim, sermorelin,glucagon, exenatide, pramlintide, iniglucerase, galsulfase, Leucotropin,molgramostirn, triptorelin acetate, histrelin (subcutaneous implant,Hydron), deslorelin, histrelin, nafarelin, leuprolide sustained releasedepot (ATRIGEL), leuprolide implant (DUROS), goserelin, Eutropin, KP-102program, somatropin, mecasermin (growth failure), enlfavirtide,Org-33408, insulin glargine, insulin glulisine, insulin (inhaled),insulin lispro, insulin deternir, insulin (buccal, RapidMist),mecasermin rinfabate, anakinra, celmoleukin, 99 mTc-apcitide injection,myelopid, Betaseron, glatiramer acetate, Gepon, sargramostim,oprelvekin, human leukocyte-derived alpha interferons, Bilive, insulin(recombinant), recombinant human insulin, insulin aspart, mecasenin,Roferon-A, interferon-alpha 2, Alfaferone, interferon alfacon-1,interferon alpha, Avonex' recombinant human luteinizing hormone, dornasealpha, trafermin, ziconotide, taltirelin, diboterminalfa, atosiban,becaplermin, eptifibatide, Zemaira, CTC-111, Shanvac-B, HPV vaccine(quadrivalent), octreotide, lanreotide, ancestirn, agalsidase beta,agalsidase alpha, laronidase, prezatide copper acetate (topical gel),rasburicase, ranibizumab, Actimmune, PEG-Intron, Tricomin, recombinanthouse dust mite allergy desensitization injection, recombinant humanparathyroid hormone (PTH) 1-84 (sc, osteoporosis), epoetin delta,transgenic antithrombin III, Granditropin, Vitrase, recombinant insulin,interferon-alpha (oral lozenge), GEM-21S, vapreotide, idursulfase,omnapatrilat, recombinant serum albumin, certolizumab pegol,glucarpidase, human recombinant C1 esterase inhibitor (angioedema),lanoteplase, recombinant human growth hormone, enfuvirtide (needle-freeinjection, Biojector 2000), VGV-1, interferon (alpha), lucinactant,aviptadil (inhaled, pulmonary disease), icatibant, ecallantide,omiganan, Aurograb, pexigananacetate, ADI-PEG-20, LDI-200, degarelix,cintredelinbesudotox, Favld, MDX-1379, ISAtx-247, liraglutide,teriparatide (osteoporosis), tifacogin, AA4500, T4N5 liposome lotion,catumaxomab, DWP413, ART-123, Chrysalin, desmoteplase, amediplase,corifollitropinalpha, TH-9507, teduglutide, Diamyd, DWP-412, growthhormone (sustained release injection), recombinant G-CSF, insulin(inhaled, AIR), insulin (inhaled, Technosphere), insulin (inhaled,AERx), RGN-303, DiaPep277, interferon beta (hepatitis C viral infection(HCV)), interferon alpha-n3 (oral), belatacept, transdermal insulinpatches, AMG-531, MBP-8298, Xerecept, opebacan, AIDSVAX, GV-1001,LymphoScan, ranpirnase, Lipoxysan, lusupultide, MP52(beta-tricalciumphosphate carrier, bone regeneration), melanoma vaccine,sipuleucel-T, CTP-37, Insegia, vitespen, human thrombin (frozen,surgical bleeding), thrombin, TransMID, alfimeprase, Puricase,terlipressin (intravenous, hepatorenal syndrome), EUR-1008M, recombinantFGF-I (injectable, vascular disease), BDM-E, rotigaptide, ETC-216,P-113, MBI-594AN, duramycin (inhaled, cystic fibrosis), SCV-07, OPI-45,Endostatin, Angiostatin, ABT-510, Bowman Birk Inhibitor Concentrate,XMP-629, 99 mTc-Hynic-Annexin V, kahalalide F, CTCE-9908, teverelix(extended release), ozarelix, rornidepsin, BAY-504798, interleukin4,PRX-321, Pepscan, iboctadekin, rhlactoferrin, TRU-015, IL-21, ATN-161,cilengitide, Albuferon, Biphasix, IRX-2, omega interferon, PCK-3145,CAP-232, pasireotide, huN901-DMI, ovarian cancer immunotherapeuticvaccine, SB-249553, Oncovax-CL, OncoVax-P, BLP-25, CerVax-16,multi-epitope peptide melanoma vaccine (MART-1, gp100, tyrosinase),nemifitide, rAAT (inhaled), rAAT (dermatological), CGRP (inhaled,asthma), pegsunercept, thymosinbeta4, plitidepsin, GTP-200, ramoplanin,GRASPA, OBI-1, AC-100, salmon calcitonin (oral, eligen), calcitonin(oral, osteoporosis), examorelin, capromorelin, Cardeva, velafermin,131I-TM-601, KK-220, T-10, ularitide, depelestat, hematide, Chrysalin(topical), rNAPc2, recombinant Factor V111 (PEGylated liposomal), bFGF,PEGylated recombinant staphylokinase variant, V-10153, SonoLysisProlyse, NeuroVax, CZEN-002, islet cell neogenesis therapy, rGLP-1,BIM-51077, LY-548806, exenatide (controlled release, Medisorb),AVE-0010, GA-GCB, avorelin, ACM-9604, linaclotid eacetate, CETi-1,Hemospan, VAL (injectable), fast-acting insulin (injectable, Viadel),intranasal insulin, insulin (inhaled), insulin (oral, eligen),recombinant methionyl human leptin, pitrakinra subcutancous injection,eczema), pitrakinra (inhaled dry powder, asthma), Multikine, RG-1068,MM-093, NBI-6024, AT-001, PI-0824, Org-39141, Cpn10 (autoimmunediseases/inflammation), talactoferrin (topical), rEV-131 (ophthalmic),rEV-131 (respiratory disease), oral recombinant human insulin(diabetes), RPI-78M, oprelvekin (oral), CYT-99007 CTLA4-Ig, DTY-001,valategrast, interferon alpha-n3 (topical), IRX-3, RDP-58, Tauferon,bile salt stimulated lipase, Merispase, alaline phosphatase, EP-2104R,Melanotan-II, bremelanotide, ATL-104, recombinant human microplasmin,AX-200, SEMAX, ACV-1, Xen-2174, CJC-1008, dynorphin A, SI-6603, LABGHRH, AER-002, BGC-728, malaria vaccine (virosomes, PeviPRO), ALTU-135,parvovirus B19 vaccine, influenza vaccine (recombinant neuraminidase),malaria/HBV vaccine, anthrax vaccine, Vacc-5q, Vacc-4x, HIV vaccine(oral), HPV vaccine, Tat Toxoid, YSPSL, CHS-13340, PTH(1-34) liposomalcream (Novasome), Ostabolin-C, PTH analog (topical, psoriasis),MBRI-93.02, MTB72F vaccine (tuberculosis), MVA-Ag85A vaccine(tuberculosis), FARA04, BA-210, recombinant plague FIV vaccine, AG-702,OxSODrol, rBetV1, Der-p1/Der-p2/Der-p7 allergen-targeting vaccine (dustmite allergy), PR1 peptide antigen (leukemia), mutant ras vaccine,HPV-16 E7 lipopeptide vaccine, labyrinthin vaccine (adenocarcinoma),CIVIL vaccine, WT1-peptide vaccine (cancer), IDD-5, CDX-110, Pentrys,Norelin, CytoFab, P-9808, VT-111, icrocaptide, telbermin(dermatological, diabetic foot ulcer), rupintrivir, reticulose, rGRF,HA, alpha-galactosidase A, ACE-011, ALTU-140, CGX-1160, angiotensintherapeutic vaccine, D-4F, ETC-642, APP-018, rhMBL, SCV-07 (oral,tuberculosis), DRF-7295, ABT-828, ErbB2-specific immunotoxin(anticancer), DT3SSIL-3, TST-10088, PRO-1762, Combotox,cholecystokinin-B/gastrin-receptor binding peptides, 111In-hEGF, AE-37,trasnizumab-DM1, Antagonist G, IL-12 (recombinant), PM-02734, IMP-321,rhIGF-BP3, BLX-883, CUV-1647 (topical), L-19 basedradioimmunotherapeutics (cancer), Re-188-P-2045, AMG-386, DC/1540/KLHvaccine (cancer), VX-001, AVE-9633, AC-9301, NY-ESO-1 vaccine(peptides), NA17.A2 peptides, melanoma vaccine (pulsed antigentherapeutic), prostate cancer vaccine, CBP-501, recombinant humanlactoferrin (dry eye), FX-06, AP-214, WAP-8294A (injectable), ACP-HIP,SUN-11031, peptide YY [3-36] (obesity, intranasal), FGLL, atacicept,BR3-Fc, BN-003, BA-058, human parathyroid hormone 1-34 (nasal,osteoporosis), F-18-CCR1, AT-1100 (celiac disease/diabetes), JPD-003,PTH(7-34) liposomal cream (Novasome), duramycin (ophthalmic, dry eye),CAB-2, CTCE-0214, GlycoPEGylated erythropoietin, EPO-Fc, CNTO-528,AMG-114, JR-013, Factor XIII, aminocandin, PN-951, 716155, SUN-E7001,TH-0318, BAY-73-7977, teverelix (immediate release), EP-51216, hGH(controlled release, Biosphere), OGP-I, sifuvirtide, TV4710, ALG-889,Org-41259, rhCC10, F-991, thymopentin (pulmonary diseases), r(m)CRP,hepatoselective insulin, subalin, L19-IL-2 fusion protein, elafin,NMK-150, ALTU-139, EN-122004, rhTPO, thrombopoietin receptor agonist(thrombocytopenic disorders), AL-108, AL-208, nerve growth factorantagonists (pain), SLV-317, CGX-1007, INNO-105, oral teriparatide(eligen), GEM-OS1, AC-162352, PRX-302, LFn-p24 fusion vaccine(Therapore), EP-1043, S pneumoniae pediatric vaccine, malaria vaccine,Neisseria meningitidis Group B vaccine, neonatal group B streptococcalvaccine, anthrax vaccine, HCV vaccine (gpE1+gpE2+MF-59), otitis mediatherapy, HCV vaccine (core antigen+ISCOMATRIX), hPTH(1-34) (transdermal,ViaDerm), 768974, SYN-101, PGN-0052, aviscumnine, BIM-23190,tuberculosis vaccine, multi-epitope tyrosinase peptide, cancer vaccine,enkastim, APC-8024, GI-5005, ACC-001, TTS-CD3, vascular-targeted TNF(solid tumors), desmopressin (buccal controlled-release), onercept, andTP-9201.

In some embodiments, the polypeptide is adalimumab (HUMIRA), infliximab(REMICADE™), rituximab (RITUXAN™/MAB THERA™) etanercept (ENBREL™)bevacizumab (AVASTIN™), trastuzumab (HERCEPTIN™), pegrilgrastim(NEULASTA™), or any other suitable polypeptide including biosimilars andbiobetters.

Other suitable polypeptides are those listed below and in Table 1 ofUS2016/0097074:

TABLE 1 Protein Product Reference Listed Drug interferon gamma-1bActimmune ® alteplase; tissue plasminogen activator Activase ®/Cathflo ®Recombinant antihemophilic factor Advate human albumin Albutein ®Laronidase Aldurazyme ® interferon alfa-N3, human leukocyte derivedAlferon N ® human antihemophilic factor Alphanate ® virus-filtered humancoagulation factor IX AlphaNine ® SD Alefacept; recombinant dimericfusion Amevive ® protein LFA3-Ig Bivalirudin Angiomax ® darbepoetin alfaAranesp ™ Bevacizumab Avastin ™ interferon beta-1a; recombinant Avonex ®coagulation factor IX BeneFix ™ Interferon beta-1b Betaseron ®Tositumomab BEXXAR ® antihemophilic factor Bioclate ™ human growthhormone BioTropin ™ botulinum toxin type A BOTOX ® Alemtuzumab Campath ®acritumornab; technetium-99 labeled CEA-Scan ® alglucerase; modifiedform of Ceredase ® beta-glucocerebrosidase imiglucerase; recombinantform of Cerezyme ® beta-glucocerebrosidase crotalidae polyvalent immuneFab, ovine CroFab ™ digoxin immune fab [ovine] DigiFab ™ RasburicaseElitek ® Etanercept ENBREL ® epoietin alfa Epogen ® Cetuximab Erbitux ™algasidase beta Fabrazyme ® Urofollitropin Fertinex ™ follitropin betaFollistim ™ Teriparatide FORTEO ® human somatropin GenoTropin ® GlucagonGlucaGen ® follitropin alfa Gonal-F ® antihemophilic factor Helixate ®Antihemophilic Factor; Factor XIII HEMOFIL adefovir dipivoxil Hepsera ™Trastuzumab Herceptin ® Insulin Humalog ® antihemophilic factor/vonWillebrand Humate-P ® factor complex-human Somatotropin Humatrope ®Adalimumab HUMIRA ™ human insulin Humulin ® recombinant humanhyaluronidase Hylenex ™ interferon alfacon-1 Infergen ® eptifibatideIntegrilin ™ alpha-interferon Intron A ® Palifermin Kepivance AnakinraKineret ™ antihemophilic factor Kogenate ® FS insulin glargine Lantus ®granulocyte macrophage colony- Leukine ®/Leukine ® stimulating factorLiquid lutropin alfa for injection Luveris OspA lipoprotein LYMErix ™Ranibizumab LUCENTIS ® gemtuzumab ozogamicin Mylotarg ™ GalsulfaseNaglazyme ™ Nesiritide Natrecor ® Pegfilgrastim Neulasta ™ OprelvekinNeumega ® Filgrastim Neupogen ® Fanolesomab NeutroSpec ™ (formerlyLeuTech ®) somatropin [rDNA] Norditropin ®/Norditropin Nordiflex ®Mitoxantrone Novantrone ® insulin; zinc suspension; Novolin L ® insulin;isophane suspension Novolin N ® insulin, regular; Novolin R ® InsulinNovolin ® coagulation factor VIIa NovoSeven ® Somatropin Nutropin ®immunoglobulin intravenous Octagam ® PEG-L-asparaginase Oncaspar ®abatacept, fully human soluable fusion Orencia ™ protein muromomab-CD3Orthoclone OKT3 ® high-molecular weight hyaluronan Orthovisc ® humanchorionic gonadotropin Ovidrel ® live attenuated BacillusCalmette-Guerin Pacis ® peginterferon alfa-2a Pegasys ® pegylatedversion of interferon alfa-2b PEG-Intron ™ Abarelix (injectablesuspension); Plenaxis ™ gonadotropin-releasing hormone antagonistantagonist epoietin alfa Procrit ® Aldesleukin Proleukin, IL-2 ®Somatrem Protropin ® dornase alfa Pulmozyme ® Efalizumab; selectivereversible T-cell RAPTIVA ™ blocker combination of ribavirin and alphainterferon Rebetron ™ Interferon beta 1a Rebif ® antihemophilic factorRecombinate ® rAHF/ antihemophilic factor ReFacto ® Lepirudin Refludan ®Infliximab REMICADE ® Abciximab ReoPro ™ Reteplase Retavase ™ RituximaRituxan ™ interferon alfa-2^(a) Roferon-A ® Somatropin Saizen ®synthetic porcine secretin SecreFlo ™ Basiliximab Simulect ® EculizumabSOLARIS (R) Pegvisomant SOMAVERT ® Palivizumab; recombinantly produced,Synagis ™ humanized mAb thyrotropin alfa Thyrogen ® TenecteplaseTNKase ™ Natalizumab TYSABRI ® human immune globulin intravenousVenogiobulin-S ® 5% and 10% solutions interferon alfa-n1, lymphoblastoidWellferon ® drotrecogin alfa Xigris ™ Omalizumab; recombinant Xolair ®DNA-derived humanized monoclonal antibody targeting immunoglobulin-EDaclizumab Zenapax ® ibritumomab tiuxetan Zevalin ™ SomatotropinZorbtive ™ (Serostim ®)

In embodiments, the polypeptide is a hormone, blood clotting/coagulationfactor, cytokine/growth factor, antibody molelcule, fusion protein,protein vaccine, or peptide as shown in Table 2.

TABLE 2 Exemplary Products Therapeutic Product type Product Trade NameHormone Erythropoietin, Epoein-α Epogen, Procrit Darbepoetin-α AranespGrowth hormone (GH), Genotropin, Humatrope, Norditropin, somatotropinNovIVitropin, Nutropin, Omnitrope, Protropin, Human follicle-stimulatingSiazen, Serostim, Valtropin hormone (FSH) Gonal-F, Follistim Humanchorionic gonadotropin Ovidrel Lutropin-α Luveris Glucagon GlcaGenGrowth hormone releasing Geref hormone (GHRH) ChiRhoStim (humanpeptide), SecreFlo Secretin (porcine peptide) Thyroid stimulatinghormone Thyrogen (TSH), thyrotropin Blood Factor VIIa NovoSevenClotting/Coagulation Factor VIII Bioclate, Helixate, Kogenate,Recombinate, Factors Factor IX ReFacto Antithrombin III (AT-III) BenefixProtein C concentrate Thrombate III Ceprotin Cytokine/Growth Type Ialpha-interferon Infergen factor Interferon-αn3 (IFNαn3) Alferon NInterferon-β1a (rIFN-β) Avonex, Rebif Interferon-β1b (rIFN-β) BetaseronInterferon-γ1b (IFN γ) Actimmune Aldesleukin (interleukin Proleukin2(IL2), epidermal theymocyte Kepivance activating factor; ETAF RegranexPalifermin (keratinocyte Anril, Kineret growth factor; KGF) Becaplemin(platelet-derived growth factor; PDGF) Anakinra (recombinant IL1antagonist) Antibody molecules Bevacizumab (VEGFA mAb) Avastin Cetuximab(EGFR mAb) Erbitux Panitumumab (EGFR mAb) Vectibix Alemtuzumab (CD52mAb) Campath Rituximab (CD20 chimeric Rituxan Ab) Herceptin Trastuzumab(HER2/Neu Orencia mAb) Humira Abatacept (CTLA Ab/Fc Enbrel fusion)Remicade Adalimumab (TNFα mAb) Amevive Etanercept (TNF receptor/FcRaptiva fusion) Tysabri Infliximab (TNFα chimeric Soliris mAb)Orthoclone, OKT3 Alefacept (CD2 fusion protein) Efalizumab (CD11a mAb)Natalizumab (integrin α4 subunit mAb) Eculizumab (C5mAb) Muromonab-CD3Other: Insulin Humulin, Novolin Fusion Hepatitis B surface antigenEngerix, Recombivax HB proteins/Protein (HBsAg) Gardasilvaccines/Peptides HPV vaccine LYMErix OspA Rhophylac Anti-Rhesus(Rh)Fuzeon immunoglobulin G QMONOS Enfuvirtide Spider silk, e.g., fibrion

In embodiments, the protein is multispecific protein, e.g., a bispecificantibody as shown in Table 3.

TABLE 3 Bispecific Formats Name (other names, Proposed Diseases (orsponsoring BsAb mechanisms of Development healthy organizations) formatTargets action stages volunteers) Catumaxomab BsIgG: CD3, Retargeting ofT Approved in Malignant ascites (Removab ®, Triomab EpCAM cells totumor, Fc EU in EpCAM Fresenius Biotech, mediated effector EU positivetumors Trion Pharma, functions Neopharm) Ertumaxomab BsIgG: CD3, HER2Retargeting of T Phase I/II Advanced solid (Neovii Biotech, Triomabcells to tumor tumors Fresenius Biotech) Blinatumomab BiTE CD3, CD19Retargeting of T Approved in Precursor B-cell (Blincyto ®, AMG cells totumor USA ALL 103, MT 103, Phase II and ALL MEDI 538, III DLBCL Amgen)Phase II NHL Phase I REGN1979 BsAb CD3, CD20 (Regeneron) Solitomab (AMGBiTE CD3, Retargeting of T Phase I Solid tumors 110, MT110, EpCAM cellsto tumor Amgen) MEDI 565 (AMG BiTE CD3, CEA Retargeting of T Phase IGastrointestinal 211, MedImmune, cells to tumor adenocancinoma Amgen)RO6958688 BsAb CD3, CEA (Roche) BAY2010112 BiTE CD3, PSMA Retargeting ofT Phase I Prostate cancer (AMG 212, Bayer; cells to tumor Amgen) MGD006DART CD3, CD123 Retargeting of T Phase I AML (Macrogenics) cells totumor MGD007 DART CD3, gpA33 Retargeting of T Phase I Colorectal cancer(Macrogenics) cells to tumor MGD011 DART CD19, CD3 (Macrogenics)SCORPION BsAb CD3, CD19 Retargeting of T (Emergent cells to tumorBiosolutions, Trubion) AFM11 (Affimed TandAb CD3, CD19 Retargeting of TPhase I NHL and ALL Therapeutics) cells to tumor AFM12 (Affimed TandAbCD19, CD16 Retargeting of NK Therapeutics) cells to tumor cells AFM13(Affimed TandAb CD30, Retargeting of NK Phase II Hodgkin's Therapeutics)CD16A cells to tumor Lymphoma cells GD2 (Barbara Ann T cells CD3, GD2Retargeting of T Phase I/II Neuroblastoma Karmanos Cancer preloadedcells to tumor and Institute) with BsAb osteosarcoma pGD2 (Barbara Tcells CD3, Her2 Retargeting of T Phase II Metastatic breast Ann Karmanospreloaded cells to tumor cancer Cancer Institute) with BsAb EGFRBi-armedT cells CD3, EGFR Autologous Phase I Lung and other autologous preloadedactivated T cells solid tumors activated T cells with BsAb toEGFR-positive (Roger Williams tumor Medical Center) Anti-EGFR-armed Tcells CD3, EGFR Autologous Phase I Colon and activated T-cells preloadedactivated T cells pancreatic (Barbara Ann with BsAb to EGFR-positivecancers Karmanos Cancer tumor Institute) rM28 (University Tandem CD28,Retargeting of T Phase II Metastatic Hospital Tubingen) scFv MAPG cellsto tumor melanoma IMCgp100 ImmTAC CD3, peptide Retargeting of T PhaseI/II Metastatic (Immunocore) MHC cells to tumor melanoma DT2219ARL 2scFv CD19, CD22 Targeting of Phase I B cell leukemia (NCI, University oflinked to protein toxin to or lymphoma Minnesota) diphtheria tumor toxinXmAb5871 BsAb CD19, (Xencor) CD32b NI-1701 BsAb CD47, CD19 (NovImmune)MM-111 BsAb ErbB2, (Merrimack) ErbB3 MM-141 BsAb IGF-1R, (Merrimack)ErbB3 NA (Merus) BsAb HER2, HER3 NA (Merus) BsAb CD3, CLEC12A NA (Merus)BsAb EGFR, HER3 NA (Merus) BsAb PD1, undisclosed NA (Merus) BsAb CD3,undisclosed Duligotuzumab DAF EGFR, Blockade of 2 Phase I and II Headand neck (MEHD7945A, HER3 receptors, ADCC Phase II cancer Genentech,Roche) Colorectal cancer LY3164530 (Eli Not EGFR, MET Blockade of 2Phase I Advanced or Lily) disclosed receptors metastatic cancer MM-111HSA body HER2, Blockade of 2 Phase II Gastric and (Merrimack HER3receptors Phase I esophageal Pharmaceuticals) cancers Breast cancerMM-141, IgG-scFy IGF-1R, Blockade of 2 Phase I Advanced solid (MerrimackHER3 receptors tumors Pharmaceuticals) RG7221 CrossMab Ang2, VEGFBlockade of 2 Phase I Solid tumors (R05520985, A proangiogenics Roche)RG7716 (Roche) CrossMab Ang2, VEGF Blockade of 2 Phase I Wet AMD Aproangiogenics OMP-305B83 BsAb DLL4/VEGF (OncoMed) TF2 Dock and CEA, HSGPretargeting Phase II Colorectal, (Immunomedics) lock tumor for PET orbreast and lung radioimaging cancers ABT-981 DVD-Ig IL-la, IL-10Blockade of 2 Phase II Osteoarthritis (AbbVie) proinflammatory cytokinesABT-122 DVD-Ig TNF, IL-17A Blockade of 2 Phase II Rheumatoid (AbbVie)proinflammatory arthritis cytokines COVA322 IgG- TNF, IL17A Blockade of2 Phase I/II Plaque psoriasis fynomer proinflammatory cytokinesSAR156597 Tetravalent IL-13, IL-4 Blockade of 2 Phase I Idiopathic(Sanofi) bispecific proinflammatory pulmonary tandem IgG cytokinesfibrosis GSK2434735 Dual- IL-13, IL-4 Blockade of 2 Phase I (Healthy(GSK) targeting proinflammatory volunteers) domain cytokinesOzoralizumab Nanobody TNF, HSA Blockade of Phase II Rheumatoid (ATN103,Ablynx) proinflammatory arthritis cytokine, binds to HSA to increasehalf-life ALX-0761 (Merck Nanobody IL-17A/F, Blockade of 2 Phase I(Healthy Serono, Ablynx) HSA proinflammatory volunteers) cytokines,binds to HSA to increase half-life ALX-0061 Nanobody IL-6R, HSA Blockadeof Phase I/II Rheumatoid (AbbVie, Ablynx; proinflammatory arthritiscytokine, binds to HSA to increase half-life ALX-0141 Nanobody RANKL,Blockade of bone Phase I Postmenopausal (Ablynx, HSA resorption, bindsbone loss Eddingpharm) to HSA to increase half-life RG6013/ACE910 ART-IgFactor IXa, Plasma Phase II Hemophilia (Chugai, Roche) factor Xcoagulation

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which the disclosure pertains. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice of and/or for the testing of the present disclosure, thepreferred materials and methods are described herein. In describing andclaiming the present disclosure, the following terminology will be usedaccording to how it is defined, where a definition is provided.

It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “a modular unit” can mean one modular unitor more than one modular unit.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and illustrativeexamples, make and utilize the customizable facility of the presentdisclosure.

While this invention has been disclosed with reference to specificaspects, it is apparent that other aspects and variations of thisinvention may be devised by others skilled in the art without departingfrom the true spirit and scope of the invention. The appended claims areintended to be construed to include all such aspects and equivalentvariations.

What is claimed is:
 1. A method of reducing a time-to-market of apharmaceutical product, the method comprising: providing a campus forfabricating at least a first and a second pharmaceutical product, thecampus including a plurality of customizable facilities configured tomanufacture the at least first and second pharmaceutical products, amedia/buffer plant separate from the plurality of customizablefacilities, and a utility building separate from the media/buffer plantand the plurality of customizable facilities, the utility building beingconnected by at least one utility line to the media/buffer plant and theplurality of customizable facilities to provide at least one firstutility via the at least one utility line, each customizable facilityincluding: at least one central unit positioned on a floor of thecustomizable facility; and a plurality of modular units in communicationwith the at least one central unit such that the at least one centralunit is configured to provide shared utilities to each modular unit, atleast one modular unit of the plurality of modular units including aclean room, the at least one modular unit being configured forpharmaceutical product manufacturing, the at least one modular unitbeing one of: a fermentation unit, a pre-viral unit, and a post-viralunit; and wherein the plurality of customizable facilities includes afirst customizable facility configured to manufacture the firstpharmaceutical product and a second customizable facility configured tomanufacture the second pharmaceutical product different from the firstpharmaceutical product, and wherein the availability of the secondcustomizable facility configured to manufacture the secondpharmaceutical product allows a manufacturer of the secondpharmaceutical to reduce time-to-market of the second pharmaceuticalproduct by at least 12 months.
 2. The method of claim 1, wherein the atleast one central unit provides at least one second utility to theplurality of modular units.
 3. The method of claim 1, further comprisingproviding a warehouse adjacent one of the customizable facilities. 4.The method of claim 1, wherein the at least one first utility includesat least one of: steam and an air supply.
 5. The method of claim 1,wherein providing a plurality of customizable facilities includesproviding a customizable facility by providing a shell, positioning theat least one central unit at least partially within the shell, andpositioning at least one of the plurality of modular units at leastpartially within the shell.
 6. The method of claim 1, wherein theplurality of modular units includes at least one of a fermentation unit,a pre-viral unit, a post-viral unit, a utility space, a warehouse, amedia buffer facility, an office, a personnel unit, a production unit, afill-finish unit, a dosage formulation unit, and a packaging unit. 7.The method of claim 2, wherein a first utility of the at least one firstutility is the same as a second utility of the at least one secondutility.
 8. The method of claim 2, wherein a first utility of the atleast one first utility is different from a second utility of the atleast one second utility.
 9. The method of claim 5, wherein providingthe plurality of modular units includes providing a plurality of modularunits arranged to maximize a number of modular units within the shellwhile minimizing a footprint of the shell.
 10. The method of claim 1,further comprising positioning the media/buffer plant adjacent one ofthe customizable facilities, and positioning the utility buildingadjacent one of the customizable facilities.
 11. The method of claim 5,wherein an outer wall of the customizable facility is one of formed bythe shell, the shell entirely enclosing the at least one central unitand at least one modular unit of the plurality of modular units, andformed by the shell and at least one of an outer wall of the at leastone central unit and an outer wall of the at least one modular unit. 12.The method of claim 5, wherein the shell includes at least one sidewall, the at least one side wall encircling the at least one centralunit and the plurality of modular units, and a roof secured to an upperedge of the at least one side wall, the roof extending over the at leastone central unit and the plurality of modular units.
 13. A customizablefacility for manufacturing at least one pharmaceutical product,including five rows of zones, comprising: a first row including aplurality of purification zones; a second row including a plurality offermentation zones; a third row including at least one central utilityzone; a fourth row including a plurality of fermentation zones; and afifth row including a plurality of purification zones.
 14. Thecustomizable facility of claim 13, wherein the facility does not includea shell.
 15. The customizable facility of claim 13, wherein the centralutility zone provides utilities to each of the other zones.
 16. Thecustomizable facility of claim 13, wherein the first row includes threepurification zones, the second row includes three fermentation zones,the fourth row includes three fermentation zones, and/or the fifth rowincludes three purification zones.
 17. The customizable facility ofclaim 16, further including an extension that adds two additionalpurification zones to the first row, two additional fermentation zonesto the second row, two additional fermentation zones to the fourth row,and/or two additional purification zones to the fifth row.
 18. Thecustomizable facility of claim 17, further including an extension thatadds an additional utility zone to the third row.
 19. The customizablefacility of claim 13, further including a shell enclosing all of thefirst through fifth rows.
 20. The customizable facility of claim 13,wherein the second row is adjacent the first row, the third row isadjacent the second row, the fourth row is adjacent the third row, andthe fifth row is adjacent the fourth row.